Bicalutamide

Androgen Receptor Binding Dynamics and Specificity

Bicalutamide's mechanism involves intricate binding dynamics with the AR, characterized by competitive inhibition, differential binding affinity, and the crucial role of its R-enantiomer.

This compound acts as a selective, competitive, and silent antagonist of the androgen receptor. wikipedia.orgwikipedia.org It competes with endogenous androgens, such as testosterone and dihydrotestosterone (DHT), for binding to the AR in target tissues. wikipedia.orgcancer-research-network.com By occupying the ligand-binding pocket of the AR, this compound prevents androgens from binding and activating the receptor, thereby inhibiting their downstream effects and curbing the growth of androgen-dependent cells, including prostate cancer cells. researchgate.netcancer-research-network.com

While this compound is a potent AR antagonist, its binding affinity for the AR is considerably lower than that of the main endogenous ligand, DHT. DHT's half-maximal inhibitory concentration (IC50) for the AR is approximately 3.8 nM, whereas this compound's IC50 ranges from 159 to 243 nM, indicating that this compound has an affinity approximately 30 to 100 times lower than DHT. wikipedia.orgwikipedia.org

Despite this lower affinity, this compound can effectively prevent AR activation by androgens when present in sufficiently high relative concentrations (1,000- to 10,000-fold excess). wikipedia.org

Compared to other first-generation nonsteroidal antiandrogens, this compound generally exhibits higher binding affinity:

Hydroxyflutamide (active metabolite of flutamide): this compound has a 4-fold greater affinity for the AR than hydroxyflutamide. wikipedia.orgnih.gov

Nilutamide: this compound has a 5-fold higher affinity than nilutamide. wikipedia.org

However, newer, second-generation antiandrogens like enzalutamide show significantly higher binding affinities than this compound. Enzalutamide, for instance, has a 5- to 8-fold higher affinity for the AR compared to this compound. wikipedia.orgjhoponline.comascopubs.orgnih.gov Apalutamide also demonstrates 7- to 10-fold greater affinity for the AR than this compound. jhoponline.comnih.gov

Table 1: Relative Binding Affinities of Antiandrogens to Androgen Receptor

This compound is administered as a racemic mixture, but its antiandrogenic activity resides almost exclusively in the (R)-enantiomer, R-bicalutamide. wikipedia.orgwikipedia.orgpnas.orgmedchemexpress.comnih.gov The R-isomer binds to the androgen receptor with an affinity that is approximately 30-fold higher than that of the (S)-isomer. wikipedia.orgpnas.orgmedchemexpress.comnih.govacs.org Furthermore, at steady-state, the plasma levels of the (R)-isomer are notably 100-fold higher than those of the (S)-isomer. wikipedia.org This pronounced difference in binding affinity and plasma concentration underscores R-bicalutamide as the primary active moiety responsible for the drug's antiandrogenic effects. wikipedia.orgpnas.orgmedchemexpress.comnih.gov

Impact on Androgen Receptor Conformational States

This compound binding induces specific conformational changes in the androgen receptor, which are critical for its antagonistic action.

A widely proposed mechanism for AR antagonism, supported by molecular dynamics simulations and X-ray crystal structures, involves the perturbation and displacement of Helix 12 (H12) within the AR ligand-binding domain (LBD) upon antagonist binding. researchgate.netnih.govresearchgate.netacs.orgnih.gov In the normal agonist-bound state, H12, along with helices H3 and H4, forms a crucial region known as the activation function-2 (AF2) site, which is essential for coactivator binding and subsequent transcriptional activation. researchgate.netnih.gov

When this compound binds to the AR, it accesses an additional binding pocket (B-site) adjacent to the hormone binding site, which induces the displacement of H12. researchgate.netnih.gov This displacement distorts the AF2 site, rendering it unsuitable for the binding of coactivator proteins. researchgate.netnih.govresearchgate.netacs.orgnih.govnih.gov This disruption of coactivator binding is a key mechanism by which this compound inactivates AR-dependent transcription. researchgate.netnih.govacs.orgnih.gov Molecular dynamics simulations have shown that this compound binding can cause residues like Lys720, Val716, and Gln733 to move, further disturbing the charge clump in the AF2 site and preventing co-activator association. nih.gov

While this compound is known to stabilize AR association with cytosolic heat shock protein complexes, it has been observed that this compound can still stimulate AR nuclear translocation. nih.gov Furthermore, specific DNA binding by the this compound-liganded AR has been demonstrated in vivo. cancer-research-network.comnih.gov This suggests that this compound does not primarily inhibit AR function by preventing its nuclear import or its ability to bind DNA. Instead, its antagonistic action primarily stems from its ability to recruit corepressors rather than coactivators, leading to the assembly of a transcriptionally inactive receptor, even when the AR is localized in the nucleus and bound to DNA. researchgate.netnih.gov In contrast, second-generation antiandrogens like enzalutamide actively inhibit AR nuclear translocation and its binding to DNA, representing a mechanistic difference from this compound. jhoponline.comascopubs.orgwikipedia.org

Effects on Androgen Receptor Signaling Pathways

This compound's primary mechanism involves the direct competitive inhibition of androgen binding to the AR, thereby disrupting the entire androgen receptor signaling cascade. patsnap.comdrugbank.com

Androgen receptors typically form homodimers upon the binding of an agonist, a critical step for their function as transcription factors. researchgate.net The binding of this compound to the androgen receptor monomers has been shown to induce significant instability within the homodimer structure. researchgate.net This instability can lead to the dissociation of the monomers, which in turn prevents the AR from effectively migrating into the nucleus and initiating its transcriptional activity. researchgate.net Beyond competitive antagonism, this compound has also been observed to accelerate the degradation of the androgen receptor protein, further contributing to its antiandrogenic effects. wikipedia.org This modulation of AR functionality is influenced by various factors, including the formation of heat shock protein (HSP) complexes and receptor dimerization. mdpi.com

By preventing the androgen receptor from translocating to the nucleus and binding to DNA, this compound directly impacts the downstream signaling cascades that are typically initiated by AR-mediated gene transcription. patsnap.comexplorationpub.com This includes the attenuation of coactivator mobilization, which is necessary for full AR transcriptional activity. mdpi.commdpi.com The disruption of AR signaling by this compound can indirectly influence other cellular pathways. For instance, in the context of this compound resistance, alterations in downstream signaling pathways, such as the PI3K/AKT/mTOR pathway and Wnt/β-catenin signaling, have been observed to become more prominent as cells adapt to the blocked AR activity. explorationpub.commdpi.comnih.govkarger.com This highlights the intricate network of cellular signaling and how the inhibition of a key pathway like AR signaling can lead to compensatory changes in other cascades.

Table 1: Androgen Receptor Binding Affinities and Potencies

Table 2: Effects of this compound on Cell Viability and Gene Expression

Pharmacodynamic Profile of R-Bicalutamide

Bicalutamide's therapeutic action is almost exclusively mediated by its (R)-enantiomer. geneesmiddeleninformatiebank.nlfda.govaccord-healthcare.asiacancercareontario.cahres.ca

The (R)-enantiomer of this compound is characterized as a pure, nonsteroidal antiandrogen. geneesmiddeleninformatiebank.nlaccord-healthcare.asiacancercareontario.cahres.cadrugbank.comnih.gov Its mechanism of action involves competitively binding to androgen receptors (AR) located in target tissues. fda.govhres.cadrugbank.comncats.iocancercareontario.ca By occupying these receptors, (R)-bicalutamide effectively inhibits the actions of endogenous androgens, such as testosterone and dihydrotestosterone (DHT), thereby preventing the androgen-stimulated gene expression that contributes to the growth of normal and malignant prostatic tissue. geneesmiddeleninformatiebank.nlfda.govaccord-healthcare.asiahres.cadrugbank.comnih.govcancercareontario.ca This competitive antagonism ultimately leads to the regression of prostatic tumors. geneesmiddeleninformatiebank.nlfda.govaccord-healthcare.asiahres.cadrugbank.comnih.gov

(R)-bicalutamide is considered devoid of hormonal agonist activity in wild-type androgen receptors. nih.govwikipedia.orgwikipedia.orgascopubs.org It functions as a selective competitive silent antagonist of the androgen receptor, meaning it does not activate the receptor. wikipedia.org This lack of agonist activity is a key characteristic of its action on unmutated androgen receptors. ascopubs.orgoup.com However, it is important to note that certain mutations in the androgen receptor, such as W741C, W741L, and T877A, have been shown to convert this compound from an antagonist into an agonist, a phenomenon implicated in drug resistance and antiandrogen withdrawal syndrome. aacrjournals.orgcardiff.ac.ukresearchgate.netrcsb.org

Unlike agents that suppress hormone production, this compound, as a pure antiandrogen, does not inhibit the synthesis of androgens. wikipedia.org Instead, its competitive blockade of androgen receptors disrupts the normal negative feedback loop on the hypothalamic-pituitary-gonadal axis. wikipedia.org This disruption leads to an increase in the circulating levels of gonadotropins, specifically luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and consequently, an elevation in endogenous sex hormones, including testosterone and estradiol. fda.govwikipedia.orgresearchgate.nethres.ca While testosterone levels can increase by up to 80%, they typically remain within the normal physiological range for most patients. researchgate.nethres.ca This unique endocrine state, characterized by elevated gonadotropins and gonadal steroids, is often referred to as "hypergonadotropic hypergonadism." wikipedia.org

Pharmacokinetic Characteristics of this compound

This compound is well-absorbed following oral administration, though its absolute bioavailability is not precisely known. geneesmiddeleninformatiebank.nlfda.govaccord-healthcare.asiahres.cadrugbank.comncats.iocancercareontario.canih.govdrugs.com Food does not significantly impact its absorption. geneesmiddeleninformatiebank.nlfda.govcancercareontario.cahres.cacancercareontario.caresearchgate.netnih.gov The drug is highly bound to plasma proteins, with the racemate being approximately 96% protein-bound and the (R)-enantiomer specifically binding at about 99.6%. geneesmiddeleninformatiebank.nlfda.govaccord-healthcare.asiahres.cadrugbank.comcancercareontario.cahres.cadrugs.comijbio.com

This compound undergoes stereospecific metabolism in the liver. geneesmiddeleninformatiebank.nlfda.govaccord-healthcare.asiadrugbank.comncats.iocancercareontario.canih.govdrugs.comdrugs.comijbio.comnih.gov The (S)-enantiomer, which is essentially inactive, is rapidly cleared, primarily through glucuronidation. geneesmiddeleninformatiebank.nlfda.govaccord-healthcare.asiadrugbank.comncats.iocancercareontario.canih.govdrugs.comdrugs.comijbio.comnih.gov In contrast, the active (R)-enantiomer is cleared much more slowly. Its major metabolic pathway involves oxidation to an inactive metabolite, followed by subsequent glucuronidation. geneesmiddeleninformatiebank.nlfda.govaccord-healthcare.asiadrugbank.comncats.ionih.govdrugs.comdrugs.comnih.gov Direct glucuronidation is considered a minor pathway for the (R)-enantiomer. geneesmiddeleninformatiebank.nlnih.gov Both the parent compound and its glucuronidated metabolites are eliminated from the body in approximately equal proportions via urine and feces. geneesmiddeleninformatiebank.nlfda.govaccord-healthcare.asiahres.cancats.iocancercareontario.canih.govdrugs.comnih.gov

The (R)-enantiomer of this compound exhibits a prolonged plasma elimination half-life, typically around one week (approximately 5.8 to 7 days). geneesmiddeleninformatiebank.nlfda.govaccord-healthcare.asiahres.cadrugbank.comnih.govcancercareontario.caresearchgate.netdrugs.comijbio.com This extended half-life leads to significant accumulation of the (R)-enantiomer in plasma upon daily administration, with approximately a 10-fold increase observed. geneesmiddeleninformatiebank.nlfda.govaccord-healthcare.asiahres.canih.govcancercareontario.caresearchgate.nethres.ca At steady state, the predominantly active (R)-enantiomer constitutes approximately 99% of the total circulating this compound enantiomers. geneesmiddeleninformatiebank.nlfda.govaccord-healthcare.asiahres.cancats.ioresearchgate.netnih.govdrugs.comdrugs.comijbio.com For example, daily administration of 50 mg of this compound typically results in steady-state plasma concentrations of the (R)-enantiomer of approximately 9 µg/mL. geneesmiddeleninformatiebank.nlaccord-healthcare.asiahres.canih.govhres.ca The pharmacokinetics of the (R)-enantiomer are generally not affected by age, renal impairment, or mild to moderate hepatic impairment; however, severe hepatic impairment can result in slower elimination of the (R)-enantiomer. geneesmiddeleninformatiebank.nlfda.govaccord-healthcare.asiahres.canih.govcancercareontario.caresearchgate.nethres.cadrugs.com

Table 1: Key Pharmacokinetic Parameters of this compound Enantiomers

In Vitro Investigations on Cancer Cell Lines

Bicalutamide's efficacy has been evaluated across various cancer cell lines, primarily focusing on its ability to modulate androgen receptor signaling and induce cellular changes.

Animal Model Studies in Androgen-Dependent Cancers

Animal models have been instrumental in understanding this compound's in vivo effects on tumor growth and accessory sex organ size.

Efficacy Studies in Prostate Cancer

Efficacy studies have characterized bicalutamide's impact on disease progression, biochemical markers, and patient survival across diverse prostate cancer cohorts.

Table 1: Efficacy of this compound 150 mg Adjuvant to Radiotherapy in Locally Advanced Prostate Cancer

Combined androgen blockade (CAB), involving this compound alongside LHRH analogues, has been compared with LHRH analogue monotherapy and other antiandrogen combinations. A large randomized study comparing this compound (50 mg once daily) with flutamide, both in combination with LHRH analogues, demonstrated superior efficacy for this compound in terms of time to treatment failure in patients with untreated metastatic (Stage D2) prostate cancer. nih.govnih.govkarger.com At a median follow-up of 49 weeks, the time to treatment failure was significantly better for the this compound group (P = 0.005), with patients in the flutamide group being 34% more likely to experience treatment failure. nih.gov

This compound 150 mg, whether as immediate therapy alone or as an adjuvant to curative treatment, has been shown to significantly reduce the risk of disease progression and PSA doubling in patients with localized or locally advanced prostate cancer. clinicsinoncology.com In the context of locally advanced disease, this compound adjuvant to radiotherapy significantly reduced the risk of PSA progression by 59% and objective progression by 44%. researchgate.netnih.gov

Across various studies, this compound 150 mg significantly improved progression-free survival (HR 0.85, 95% CI 0.79-0.91; P= 0.001) in patients with localized or locally advanced prostate cancer over a median follow-up of 9.7 years, with the benefit predominantly observed in locally advanced disease. nih.gov For biochemical recurrence after radical prostatectomy, this compound combined with radiation therapy reduced the risk of progression and metastatic disease. onclive.com Freedom from progression was documented in 57% of patients receiving radiation therapy plus this compound, compared to 40% for radiation therapy alone (P <.0001). onclive.com

A phase II trial investigating this compound with or without metformin for biochemically recurrent prostate cancer showed PSA responses in 50% of patients receiving metformin monotherapy after 8 weeks, but no significant difference in PSA at 32 weeks between the this compound alone and this compound plus metformin arms. ascopubs.orgnih.gov Additionally, adding docetaxel to this compound (150 mg daily) improved progression-free survival (HR 0.68, 95% CI 0.50–0.93; p = 0.015) in hormone-naïve non-metastatic prostate cancer with rising PSA, particularly in patients with PSA relapse after prior local therapy (HR 0.67, 95% CI 0.49–0.94; p = 0.019). tandfonline.com The 5-year progression-free survival was 49% for the this compound plus docetaxel group, compared to 36% for the this compound alone group. tandfonline.com

Table 2: Impact of this compound on Progression-Free Survival in Prostate Cancer

Comparative Clinical Effectiveness with Other Antiandrogens and Therapies

This compound's clinical effectiveness has been compared to other antiandrogens and therapeutic approaches, highlighting its relative strengths and weaknesses within the prostate cancer treatment landscape.

Compared to other first-generation non-steroidal antiandrogens (NSAAs) like flutamide and nilutamide, this compound generally exhibits improved potency, efficacy, tolerability, and safety, leading to its widespread adoption in clinical practice. wikipedia.org In combination with LHRH analogues, this compound demonstrated superior efficacy to flutamide in terms of time to treatment failure in metastatic prostate cancer. nih.govnih.govkarger.com

When compared to second-generation NSAAs such as enzalutamide and apalutamide, this compound is generally considered to have inferior potency and efficacy, although it maintains similar tolerability and safety profiles with a lower propensity for drug interactions. wikipedia.org In castration-resistant prostate cancer (CRPC), enzalutamide significantly prolonged progression-free survival compared to this compound. ascopost.comascopubs.org For nonmetastatic CRPC, the median PFS was not reached with enzalutamide versus 8.6 months with this compound (HR 0.24). ascopubs.org In metastatic CRPC, the median PFS was 16.5 months with enzalutamide versus 5.5 months with this compound (HR 0.24). ascopubs.org A phase II randomized trial (TERRAIN) confirmed the superior efficacy of enzalutamide over this compound in metastatic CRPC, with a median PFS of 15.7 months for enzalutamide versus 5.8 months for this compound (HR = 0.44, P < .0001). ascopost.comamegroups.org

In metastatic hormone-sensitive prostate cancer (mHSPC), enzalutamide and apalutamide significantly prolonged PSA-PFS and CRPC-PFS when compared with this compound. nih.gov However, abiraterone did not show a significant advantage over this compound in delaying disease progression in this context. nih.gov A retrospective study in Japanese patients with high-risk mCSPC indicated a higher rate of castration-resistant prostate cancer development with this compound plus ADT (50.6%) compared to abiraterone plus ADT (25.2%), with significantly longer median PFS for abiraterone (not reached) versus this compound (13.6 months). urotoday.com Rezvilutamide has also demonstrated superior efficacy over this compound in high-volume mHSPC, showing statistically significant improvements in both PFS and OS. amegroups.org

Compared to steroidal antiandrogens like cyproterone acetate and spironolactone, this compound exhibits better selectivity in its action, superior efficacy as an androgen receptor antagonist, and improved tolerability. wikipedia.org this compound also presents a better safety profile than cyproterone acetate. wikipedia.org

Table 3: Comparative Efficacy of this compound vs. Other Antiandrogens in CRPC

Investigational Applications in Other Malignancies

Beyond prostate cancer, this compound is being investigated for its potential therapeutic role in other androgen-sensitive tumors, particularly those expressing the androgen receptor.

Androgen Receptor-Centric Resistance Mechanisms

The androgen receptor plays a central role in prostate cancer progression and, consequently, in the development of resistance to AR-targeted therapies like bicalutamide. Modifications to the AR itself are key drivers of this resistance. acs.orgnih.govfrontiersin.org

Increased expression of the androgen receptor is a significant mechanism of this compound resistance. Studies have shown that some patients develop resistance due to an increase in AR expression without the presence of mutations in the AR sequence. nih.gov Overexpression of AR can hypersensitize tumor cells to very low levels of androgens, allowing the AR signaling pathway to remain active even in conditions of extremely low exogenous androgen supply. researchgate.netnih.govnih.gov

Research has demonstrated that prolonged exposure of prostate cancer cell lines, such as LNCaP, to this compound can induce AR overexpression and androgen hypersensitivity. For instance, the LNCaP-BC2 subline, generated after prolonged this compound treatment, exhibited higher AR and phosphorylated AR (pAR210) expression compared to the parental LNCaP cells. This overexpression was associated with hypersensitivity to low levels of androgen, with proliferation stimulated by a tenfold lower concentration of androgen than required for LNCaP cells. researchgate.netnih.gov AR gene amplification, which can lead to increased AR mRNA and protein levels, has been reported in castration-resistant prostate cancer (CRPC) and contributes to hormone therapy resistance. oncotarget.com

Mutations within the ligand-binding domain (LBD) of the androgen receptor are a common cause of this compound resistance. These mutations can alter the interaction between the AR protein and its ligands, including this compound. acs.orgnih.govamegroups.org Such mutations often lead to the conversion of AR antagonists into AR agonists or allow the AR to bind with alternative ligands. amegroups.orgbioscientifica.com

Common AR mutations observed in PCa patients that contribute to this compound resistance include T877A, T877S, H874Y, and W741L/C. bioscientifica.comtandfonline.comresearchgate.net These mutations can occur anywhere within the AR-related genome, but those in the LBD tend to have more destructive effects on this compound's antagonistic action. acs.orgnih.gov

One critical mechanism of resistance is the "antagonist-to-agonist" shift of this compound, where the drug, instead of inhibiting the AR, begins to activate it, paradoxically stimulating tumor growth. acs.orgwikipedia.orgamegroups.orgaacrjournals.org This shift is primarily driven by specific mutations in the AR LBD.

For example, the W741C and W741L mutations in codon 741 of the AR LBD have been shown to convert this compound from an antagonist to an agonist. frontiersin.orgaacrjournals.orgpnas.orgnih.gov In LNCaP cell sublines (LNCaP-cxDs) cultured with this compound, these mutations emerged, leading to this compound stimulating cell growth and prostate-specific antigen (PSA) secretion. aacrjournals.org Similarly, the T877A and T878A/S mutations can also induce an antagonist-to-agonist shift for this compound and other antiandrogens. amegroups.org

The structural basis for this shift involves changes in how this compound interacts with the mutated AR. In the wild-type AR, this compound's B-ring pushes aside Helix 12 (H12), disturbing the coactivator binding site (AF2) and inactivating transcription. However, with mutations like W741L, the B-ring shifts towards the mutated residue, and Methionine 895 (M895), dragging H12, moves closer to L741. This allows H12 to cover the AR LBD, leading to an agonistic conformation and AR activation. researchgate.netnih.gov

The conformational changes in Helix 12 (H12) of the AR LBD are crucial for ligand-mediated AR activation or inhibition. H12 is the most flexible part of the AR, and its movement is directly linked to the mechanism of action of ligands. frontiersin.orgnih.gov

In the context of this compound resistance, mutations in the AR LBD, such as T877A, T877S, and H874Y, can lead to increased flexibility in the H12 helix. tandfonline.comresearchgate.netnih.gov This increased flexibility disrupts the compactness of the LBD, thereby reducing the affinity for this compound and promoting a conformation that favors AR activation, even in the presence of the antiandrogen. tandfonline.comresearchgate.netnih.gov Molecular dynamics simulations have been used to unveil how these structural alterations and changes in molecular motions of the LBD contribute to drug resistance. tandfonline.comresearchgate.netnih.gov

Androgen receptor splice variants (AR-SVs) are truncated forms of the AR that often lack the ligand-binding domain (LBD) but retain the N-terminal domain (NTD) and DNA-binding domain (DBD), allowing for constitutive, ligand-independent activation of AR signaling. mdpi.com These variants play a significant role in resistance to androgen deprivation therapy and antiandrogens like this compound. aacrjournals.orgaacrjournals.orgfrontiersin.org

AR-V7, encoded by contiguous splicing of AR exons 1/2/3/CE3, is the most common and well-studied AR splice variant linked to resistance. aacrjournals.orgaacrjournals.orgfrontiersin.org Studies have shown that this compound-resistant prostate cancer cells express significantly increased levels of AR variants, particularly AR-V7, at both mRNA and protein levels. aacrjournals.orgaacrjournals.org Exogenous expression of AR-V7 in this compound-sensitive LNCaP cells has been demonstrated to confer resistance to this compound treatment. Conversely, knocking down AR-V7 in this compound-resistant cell lines (e.g., LNCaP-BicR, CWR22Rv1) reversed this compound resistance. aacrjournals.orgaacrjournals.org AR-V7 acts as a constitutively active, ligand-independent transcription factor that can induce castration-resistant cell growth. aacrjournals.org

Epigenetic modifications, which alter gene expression without changing the underlying DNA sequence, also contribute to this compound resistance by affecting AR expression and signaling. acs.orgnih.govnih.govmdpi.com These modifications include changes in DNA methylation and histone modifications. mdpi.comamegroups.org

For example, an increase in the number of AR with phosphorylated serine at position 210 (pAR210) has been shown to induce this compound resistance by making the AR highly sensitive to small amounts of androgen. acs.orgnih.govresearchgate.net This phosphorylation is an epigenetic alteration that influences AR behavior in resistant cells. acs.orgnih.gov Furthermore, hypermethylation of the AR gene promoter can block AR expression, while hypomethylation in the promoter regions of AR target genes can lead to increased gene expression, facilitating AR reactivation even during androgen-deprivation therapy. nih.govnih.gov Histone modifications, such as altered acetylation and methylation, can modify chromatin accessibility, influencing AR transcriptional activity and promoting cancer progression despite low androgen levels. nih.govamegroups.org

Targeting epigenetic modifications is an emerging therapeutic strategy, as these changes are potentially reversible. For instance, studies have explored the use of histone deacetylase (HDAC) inhibitors, which, in combination with AR inhibitors like this compound, have shown potential to overcome resistance by affecting AR-mediated resistance mechanisms. mdpi.com

Table 1: Key Androgen Receptor (AR) Mutations and Their Impact on this compound Response

Table 2: Androgen Receptor Splice Variants and Their Role in this compound Resistance

Combination Therapeutic Approaches

Combination therapy aims to enhance the anti-tumor effect and delay or overcome resistance by simultaneously targeting multiple pathways or mechanisms.

Persistent AR signaling is a hallmark of CRPC, making co-targeting AR and its associated pathways a critical strategy. For instance, combining AR antagonists with inhibitors of molecular chaperones like Heat Shock Protein 90 (Hsp90) has shown promise. Hsp90 inhibitors, such as 17-allylamino-demethoxygeldanamycin (17-AAG) and AUY922, enhance the anti-proliferative activity of bicalutamide and enzalutamide in both androgen-sensitive and CRPC cells, inducing significant cell death at suboptimal doses bioscientifica.com. This combination also broadens the regulation of AR target genes and impairs AR chromatin binding and nuclear localization, while preventing the induction of resistance mechanisms like AR-V7 expression and the heat shock response bioscientifica.com.

Another approach involves co-targeting the PI3K/Akt/mTOR pathway, which is frequently activated in CRPC and contributes to resistance cancernetwork.comnih.gov. Studies have shown that combining mTOR inhibitors (e.g., everolimus, RAD001) with this compound can be effective, particularly in this compound-naïve CRPC patients nih.govresearchgate.net. However, resistance can still emerge due to increased eIF4E phosphorylation, which can be overcome by inhibiting its upstream kinases like Mnk1/2 or ERK1/2 researchgate.net. The combination of an AR N-terminal domain (NTD) antagonist (e.g., EPI-002) with an mTOR inhibitor (e.g., BEZ235) has also demonstrated superior anti-tumor efficacy in enzalutamide-resistant CRPC models by blocking transcriptional activities of both full-length AR and AR splice variants nih.gov.

Interleukin-6 (IL-6) signaling is also implicated in this compound resistance and progression to CRPC. Targeting IL-6, possibly through its mediator transcriptional intermediary factor 2 (TIF2), in conjunction with this compound, is suggested to provide a more effective treatment nih.govnih.gov.

Integrating this compound with chemotherapeutic agents can induce apoptosis and inhibit growth in resistant cells. For example, a combination of flutamide (another first-generation antiandrogen) with 5-fluorouracil, a pyrimidine base analogue, was found to induce apoptosis by arresting DNA biosynthesis in this compound-resistant cells nih.gov. This strategy targets downstream genes like transcription factor E2F1 and thymidylate synthase, which are key drivers of growth inhibition in resistant cells nih.gov.

Development of Novel Androgen Receptor Antagonists

The development of novel AR antagonists aims to circumvent resistance mechanisms such as AR mutations and low binding affinity of first-generation antiandrogens researchgate.netfrontiersin.org. Enzalutamide, a second-generation antiandrogen, was designed to overcome the limitations of this compound and flutamide. It exhibits a multi-pronged mechanism of action, including preventing ligand binding to AR, inhibiting AR nuclear translocation, and blocking AR binding to DNA and co-activator recruitment aacrjournals.orgoaepublish.com. Unlike this compound, enzalutamide lacks partial AR agonist activity that can occur with this compound resistance and does not recruit AR to enhancer regions or coactivators to nuclear transcription complexes aacrjournals.org. Despite these advancements, resistance to second-generation antiandrogens like enzalutamide also develops, often due to AR mutations (e.g., F877L/F876L, L702H, T878A/T877A) or AR splice variants like AR-V7 nih.govoaepublish.com.

Ongoing research focuses on designing new AR antagonists with different chemical structures to enhance AR binding affinity and overcome mutation-based resistance researchgate.netfrontiersin.org. For instance, novel 3,5-bis-trifluoromethylphenyl compounds have been designed to improve the antiproliferative activity of this compound and enzalutamide, showing improved in vitro activity against various prostate cancer cell lines while maintaining full AR antagonism researchgate.net.

Drug Repurposing for Resistance Circumvention

Drug repurposing, the strategy of finding new therapeutic uses for existing drugs, offers a faster and less costly path to new treatments due to established safety, pharmacokinetic, and pharmacodynamic profiles spandidos-publications.comaacrjournals.org. This approach has shown promise in circumventing this compound resistance.

Several investigational agents, originally approved for other conditions, have demonstrated efficacy against this compound-resistant prostate cancer:

Artesunate : An FDA-approved antimalarial drug, artesunate has shown promise in controlling prostate tumors in preclinical studies nih.gov. It is effective in suppressing castration-resistant prostate cancer (CRPC) by inhibiting AR-V7 expression, a constitutively active AR splice variant associated with resistance nih.govacs.orgrvaprostatecancersupport.org.

Niclosamide : Another antiparasitic drug, niclosamide, is a potent inhibitor of AR-V7 nih.govacs.orgaacrjournals.org. Studies show that niclosamide can resensitize this compound-resistant cells to this compound treatment by inducing AR-V7 protein degradation and reducing its recruitment to promoter regions of target genes rvaprostatecancersupport.orgaacrjournals.orgmdpi.com. Combination treatment with niclosamide and this compound has been shown to significantly induce apoptosis and inhibit tumor growth in enzalutamide-resistant cell lines rvaprostatecancersupport.orgaacrjournals.org.

Terbinafine : An antifungal medicine, terbinafine, has been found to sensitize this compound-resistant cells by altering cholesterol metabolism nih.gov. It specifically inhibits squalene epoxidase (SQLE), an enzyme involved in cholesterol biosynthesis, and its inhibition can enhance the sensitivity of prostate cancer cells to this compound researchgate.net.

Carbidopa : An inhibitor of the L-dopa decarboxylase enzyme, carbidopa, when used in combination with this compound in a prostate cancer xenograft model, resulted in a significant decrease in tumor growth (84.4% compared to the control group) nih.gov. This highlights the importance of enzymes in cellular metabolism in the context of antiandrogen resistance nih.gov.

Other repurposed drugs showing potential include chloroquine (an autophagy inhibitor) nih.gov, quercetin and curcumin (DNMT-inhibitory properties) nih.gov, and panobinostat (a histone deacetylase inhibitor) mdpi.com.

Here is a table summarizing the investigational agents and their mechanisms in overcoming this compound resistance:

Targeting Upstream and Downstream Resistance Factors

Resistance to this compound can arise from various upstream and downstream factors beyond direct AR alterations. Targeting these factors represents a promising avenue.

AR Modifications : Increased AR expression, mutations within the AR gene (e.g., W741C/L, T877A), and the presence of constitutively active AR splice variants (e.g., AR-V7) are major drivers of resistance nih.govnih.govfrontiersin.orgoaepublish.comrvaprostatecancersupport.org. Strategies include targeting the AR N-terminal domain (NTD) to block both full-length AR and AR-Vs nih.gov. Epigenetic alterations, such as increased phosphorylation of serine at position 210 (pAR210), can also induce this compound resistance by increasing sensitivity to small amounts of androgen nih.gov.

Cell Membrane and Cytoskeleton Proteins : Drug efflux transporters like ATP-binding cassette (ABC) pumps, specifically P-glycoprotein and breast cancer resistance protein (BCRP), contribute to this compound efflux from cells. Inhibiting these pumps can decrease the effective dose of this compound nih.gov. Cell adhesion proteins like protocadherin B9 and filamin A (FlnA), and microtubule-associated protein tau (MAPT), are also associated with the resistance phenotype nih.govnih.gov.

Signaling Pathways : Disturbances in various signaling pathways contribute to resistance. The Akt/mTOR pathway is frequently activated, and its inhibition can restore this compound sensitivity nih.govnih.gov. The Notch signaling pathway, through transcription factor CSL, can regulate AR activity nih.gov. Interleukin-6 (IL-6) signaling, often increased in this compound-treated cells, promotes resistance via TIF2 nih.govnih.gov. Autophagy, a process that protects prostate tumor cells against androgen inhibitors, is increased by this compound exposure, and its inhibition (e.g., with chloroquine) can restore sensitivity nih.govmdpi.com.

Epigenetic Mechanisms : Hypermethylation of the AR gene promoter can lead to loss of AR expression and this compound resistance. DNA methyltransferase (DNMT) inhibitors like 5-azacitidine, quercetin, and curcumin can induce demethylation, increase AR levels, and resensitize cells to antiandrogen drugs nih.gov.

MicroRNAs (miRNAs) : Some miRNAs are suppressed in tumor development and their restoration can inhibit tumor growth and overcome antiandrogen resistance. For instance, miR-212, which targets AR-V7, is suppressed in this compound-resistant cells, and its inhibition can decrease cytoplasmic AR-V7 concentration, resensitizing cells to this compound nih.gov. Conversely, miR-15b-3p has been found to weaken this compound sensitivity by targeting KLF2 to suppress ferroptosis, suggesting that targeting this miRNA and its downstream protein could be a new treatment strategy jcancer.org.

Enzymes and Metabolic Reprogramming : Enzymes like acyl-CoA synthetase long-chain family member 4 (ACSL4) and squalene epoxidase (SQLE) are involved in lipid metabolism and can contribute to this compound resistance nih.govresearchgate.net. Targeting these enzymes can increase drug efficacy.

Animal Toxicology Studies

Preclinical studies in various animal models have elucidated the systemic effects of bicalutamide, particularly concerning reproductive organs, hepatic function, genotoxicity, and cardiovascular parameters.

This compound's anti-androgenic activity directly impacts androgen-dependent tissues in animals. Studies have consistently shown that this compound leads to atrophy of the prostate, testis, and seminal vesicles. nih.gov This is a predictable class effect of antiandrogens and has been observed across all species examined. hpra.iehpra.iefda.govdrugs.com

In rats, this compound has been shown to cause Leydig cell hyperplasia, a result of the inhibition of pituitary feedback by testosterone. nih.gov While benign Leydig cell tumors were subsequently observed in rats, Leydig cell hyperplasia has not been reported in human patients. nih.govfda.gov

Furthermore, animal studies indicate that this compound can affect spermatogenesis, leading to reduced spermatozoa count and motility, and an increased interval to successful mating. hres.cahres.ca Testicular atrophy, specifically of the seminiferous tubules, has been observed in rats at exposures less than human therapeutic concentrations, and in dogs at higher exposures. fda.govmedsinfo.com.au Reversal of testicular atrophy has been noted in rats and dogs, though the timeframe for reversal can vary depending on the duration of exposure. hpra.iehpra.iemedsinfo.com.au In male rat offspring, reproductive toxicology studies revealed reduced anogenital distance and hypospadias at certain doses, effects consistent with other antiandrogens. fda.govhres.cahres.cahres.cadrugs.com

Table 1: Summary of this compound's Effects on Animal Reproductive Organs

This compound has been shown to cause liver enlargement and acts as a mixed-function oxidase inducer in rodents and dogs. nih.govmedsinfo.com.au These hepatic changes are considered progressions of non-neoplastic changes related to hepatic enzyme induction observed in animal toxicity studies. fda.govmedsinfo.com.au In particular, these effects have been linked to the development of thyroid hypertrophy and adenoma in rats and hepatocellular carcinoma in male mice. nih.govfda.govmedsinfo.com.au However, it is important to note that enzyme induction has not been observed in humans. nih.govhpra.iefda.govdrugs.commedsinfo.com.augeneesmiddeleninformatiebank.nl

A comprehensive battery of both in vitro and in vivo genotoxicity tests has consistently demonstrated that this compound does not exhibit genotoxic activity. nih.govfda.govdrugs.comhres.cahres.cabccancer.bc.cageneesmiddeleninformatiebank.nlastrazeneca.ca These assessments, including tests for gene mutation, and in vitro and in vivo mammalian mutation tests, have all yielded negative results. fda.govdrugs.comhres.cabccancer.bc.ca

In preclinical studies, this compound caused a reversible shortening of the electrocardiographic P-R interval in dogs. nih.govhres.ca This change was observed without any associated pathology. nih.gov However, this specific ECG change was not detected during ECG monitoring in human clinical trials. nih.gov

Human Biological Systemic Effects (Excluding Adverse Events)

Beyond animal models, the biological systemic effects of this compound have also been investigated in humans, with particular attention to its impact on the male reproductive system.

Long-term treatment with this compound (50 mg/day) in men appears to have minimal or no effect on testicular ultrastructure and spermatogenesis, even after more than four years of therapy. wikipedia.orgwikipedia.orgresearchgate.netnih.gov Studies have shown that the testicular morphology of treated patients remains unexpectedly well preserved, with normal organization of seminiferous tubules, presence of all germ line elements, and mature spermatozoa. researchgate.netnih.gov This limited impact on testicular spermatogenesis is attributed to the extremely high testosterone levels within the testes, which are largely maintained despite this compound's systemic anti-androgenic effects. wikipedia.orgwikipedia.org

However, while this compound may not significantly affect testicular spermatogenesis, it has the potential to interfere with androgen receptor-dependent sperm maturation and transport in the epididymides and vas deferens, where androgen levels are considerably lower. wikipedia.org This interference could potentially impair male fertility. wikipedia.org Although the long-term effects of this compound on male fertility have not been fully evaluated in humans, a period of subfertility or infertility should be assumed in men undergoing this compound therapy. hpra.iedrugs.comhres.cahres.cadrugs.combccancer.bc.ca

Table 2: Summary of this compound's Effects on Human Testicular Ultrastructure and Sperm Maturation

Exploration in Androgen Receptor-Positive Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive subtype of breast cancer characterized by the absence of estrogen receptors (ER), progesterone receptors (PR), and HER2/neu (HER2) amplification tbcrc.orgasco.orgnih.gov. A distinct subset of TNBC, accounting for approximately 15-25% of all TNBC cases, expresses the androgen receptor (AR) and is referred to as AR-positive TNBC tbcrc.orgasco.orgnih.govresearchgate.net. Preclinical research has identified the AR signaling pathway as a potential driver of tumor growth in this specific subtype, providing a rationale for targeting AR in these patients tbcrc.org.

Bicalutamide, an oral nonsteroidal AR antagonist, has been investigated for its therapeutic potential in AR-positive TNBC tbcrc.orgnih.govaacrjournals.org. The TBCRC 011 trial, a single-arm, non-randomized, open-label Phase II study, explored the efficacy of this compound in patients with AR-positive, ER-negative/PR-negative metastatic breast cancer tbcrc.orgnih.govaacrjournals.orgnih.gov. The study screened over 400 patients, with approximately 12% (51 out of 424) found to be AR-positive, defined by AR expression greater than 10% via immunohistochemistry tbcrc.orgnih.govnih.gov. Among the 26 evaluable patients treated with this compound, the trial demonstrated a clinical benefit rate (CBR) at 24 weeks of 19%, with a median progression-free survival (PFS) of 12 weeks nih.govnih.gov. Five patients achieved stable disease for over 6 months tbcrc.org. The therapy was reported to be well-tolerated, with no Grade 4 or 5 treatment-related adverse events nih.gov. These findings established a proof of principle for the efficacy of androgen blockade in AR-positive TNBC and laid the groundwork for further clinical investigations in this population tbcrc.orgnih.govnih.gov.

While this compound has shown promise, second-generation AR antagonists like enzalutamide, which possess a higher affinity for the AR, have also been investigated. Preliminary data from a Phase II clinical trial of enzalutamide in advanced AR-positive TNBC reported a 42% clinical benefit rate at 16 weeks spandidos-publications.com. Some studies suggest that enzalutamide may offer superior progression-free survival compared to this compound in comparable patient populations nih.gov.

Table 1: Key Clinical Data for this compound in AR-Positive TNBC

Research into Androgen Blockade for Viral Entry and Replication (e.g., SARS-CoV-2)

The observed disparity in COVID-19 incidence and severity, with men generally experiencing higher rates of infection and more severe outcomes than women, has led to investigations into the role of androgens in viral susceptibility aacrjournals.orgcancerworld.netxiahepublishing.complos.org. The SARS-CoV-2 virus, responsible for COVID-19, gains entry into host cells primarily through the interaction of its spike protein with two host cell-surface proteins: angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) aacrjournals.orgcancerworld.netxiahepublishing.com. Notably, TMPRSS2 is an androgen-driven gene, highly upregulated in prostate cancer, and its expression can be influenced by androgen levels aacrjournals.orgcancerworld.netxiahepublishing.comnih.govmedicaljournalssweden.se. This mechanistic link suggested that androgen blockade could potentially reduce viral entry and replication by downregulating these crucial host proteins aacrjournals.orgcancerworld.netxiahepublishing.complos.orgresearchgate.net.

Preclinical studies have provided evidence supporting this hypothesis. Researchers observed a decrease in mRNA levels of both TMPRSS2 and ACE2 in the lung tissue of castrated mice aacrjournals.org. Furthermore, studies in human lung cell lines demonstrated that TMPRSS2 and ACE2 expression is regulated by the androgen receptor aacrjournals.org. Androgen antagonists, including this compound and enzalutamide, have been shown to induce a mild reduction in the expression of TMPRSS2, ACE2, and furin in mouse nasal mucosa xiahepublishing.com.

Epidemiological observations also fueled this line of research. An Italian study, for instance, reported that prostate cancer patients receiving androgen deprivation therapy (ADT) had a significantly lower incidence of COVID-19 compared to prostate cancer patients not on ADT or those with other cancer types aacrjournals.orgcancerworld.netxiahepublishing.com.

Despite the promising preclinical and epidemiological signals, clinical trial data have yielded mixed results regarding the direct therapeutic benefit of androgen blockade in COVID-19. The RECOVER trial was designed to evaluate this compound in combination with best supportive care for COVID-19 in both men and women aacrjournals.org. However, a Phase II randomized, double-blind, placebo-controlled clinical trial, the Hormonal Intervention for the Treatment in Veterans with COVID-19 Requiring Hospitalization (HITCH) study (NCT04397718), did not demonstrate that rapid suppression of serum androgen levels to a castrate range significantly impacted the clinical outcomes of men hospitalized for COVID-19 xiahepublishing.com.

Furthermore, a large national population-based nested case-control study conducted in Sweden found no clear evidence to support the hypothesis that ADT, including this compound monotherapy, was associated with a reduced risk of death from COVID-19 plos.orgmedicaljournalssweden.seresearchgate.net. A systematic review of antiandrogens as therapies for COVID-19 concluded that while some in vitro studies suggested a role, subsequent in vivo studies often disproved these findings, and antiandrogens are generally not recommended for the prevention or treatment of COVID-19 nih.govresearchgate.net.

Studies on Combination Therapies with Non-Hormonal Agents

The modest response rates observed with single-agent antiandrogen therapy in AR-positive TNBC suggest that anti-androgen resistance can occur in many of these tumors, highlighting the potential benefit of combination therapies with non-hormonal agents aacrjournals.org.

Several studies have explored this compound in combination with various non-hormonal drugs:

This compound + Palbociclib: This combination has been investigated in AR-positive metastatic breast cancer. Preclinical data indicated that palbociclib, a CDK4/6 inhibitor, reduces the growth of AR-positive, ER-negative/PR-negative MDA-MB-453 breast cancer cells ascopubs.org. AR-positive TNBC is known to express a luminal profile and possess an intact retinoblastoma (Rb) protein, which is the target of palbociclib's activity ascopubs.org. A Phase I/II trial (NCT02605486) evaluated this compound (150 mg daily) combined with palbociclib (125 mg daily, 3 weeks on/1 week off) in postmenopausal patients with AR-positive TNBC ascopubs.org. The study met its prespecified endpoint, with 11 out of 33 patients being progression-free at 6 months, including 10 cases of stable disease lasting over 6 months and 1 partial response ascopubs.org. The combination was well-tolerated, with common toxicities such as leukopenia, neutropenia, lymphocytopenia, and thrombocytopenia, primarily attributed to palbociclib ascopubs.org.

This compound + Ribociclib: Another CDK inhibitor, ribociclib, has been studied in combination with this compound in AR-positive TNBC, based on the hypothesis that CDK inhibition could enhance the activity of anti-androgens aacrjournals.org. A Phase I trial investigated this compound (150 mg daily) along with ribociclib at various dose levels aacrjournals.org. The combination was found to be tolerable without unexpected toxicities, with common adverse events including neutropenia, hypertension, and lymphopenia, consistent with the known profile of ribociclib aacrjournals.org.

This compound + Doxorubicin and Docetaxel: Preclinical studies have explored the addition of this compound to conventional chemotherapy agents like doxorubicin and docetaxel in inflammatory mammary cancer (IMC) and inflammatory breast cancer (IBC) cell lines mdpi.com. In vitro assays showed that a human IBC-TN cell line (SUM149) exhibited greater sensitivity to all tested drugs, while a canine IMC-TN cell line (IPC-366) showed significant reductions only with docetaxel alone or in combination mdpi.com. The addition of this compound to doxorubicin and docetaxel combinations demonstrated potential for treating IMC and IBC, partly by increasing intratumoral testosterone levels, which have been linked to reduced tumor progression mdpi.com.

This compound + Curcumin: Research has also explored the combination of this compound with curcumin in AR-positive TNBC cells nih.gov. This preclinical study found that curcumin significantly suppressed the Wnt signaling pathway and inhibited AR protein expression in these cells nih.gov. The combination treatment of curcumin and this compound resulted in a robust increase in apoptosis and more effectively suppressed the growth of AR-positive TNBC cells compared to either drug administered alone nih.gov.

This compound + Panobinostat: In the context of castration-resistant prostate cancer (CRPC), preclinical studies have shown that panobinostat, a histone deacetylase inhibitor (HDACI), can reverse resistance to this compound aacrjournals.org. Panobinostat effectively reduced overexpressed AR mRNA and protein levels in this compound-resistant LNCaP cells aacrjournals.org. When combined, this compound and panobinostat induced synergistic growth arrest and apoptosis, suggesting that epigenetic modulation can overcome drug resistance aacrjournals.org. A clinical Phase I/II study in CRPC patients resistant to second-line AR-targeted therapies demonstrated that a 40 mg panobinostat/bicalutamide regimen increased progression-free survival and was tolerable aacrjournals.org. While this specific application is in prostate cancer, it illustrates this compound's potential in combination with non-hormonal agents to overcome resistance mechanisms.

Table 2: Investigational Combination Therapies with this compound

Development of Next-Generation Androgen Receptor Modulators

The development of next-generation androgen receptor (AR) modulators is a critical area of research, driven by the need to overcome resistance to current antiandrogens like bicalutamide. While this compound primarily targets the ligand-binding domain (LBD) of the AR, resistance often arises from AR mutations, overexpression, or alternative splicing, which can lead to continued AR signaling despite androgen deprivation tandfonline.comacs.orgoaepublish.comresearchgate.net.

Future directions in AR modulator development include:

Targeting Non-Canonical Sites: Research is exploring compounds that target sites on the AR other than the LBD, such as the N-terminal domain (NTD) or the DNA-binding domain (DBD) tandfonline.comnih.govresearchgate.net. The NTD, despite its intrinsically disordered nature, is being investigated for novel inhibitor development nih.gov. Similarly, the DBD, when crystallized in complex with DNA binding motifs, offers a reliable platform for receptor-based drug design kuleuven.be.

Selective Androgen Receptor Degraders (SARDs) and Proteolysis Targeting Chimeras (PROTACs): These novel approaches aim to degrade the AR protein rather than just blocking its activity nih.govresearchgate.netmdpi.commdpi.com. PROTACs, for instance, induce the degradation of the AR, offering a promising strategy to overcome resistance mechanisms, including those driven by AR amplification or mutation in metastatic castration-resistant prostate cancer (mCRPC) mdpi.comarvinas.com. ARV-110 (luxdegalutamide) is an oral PROTAC that has reached Phase II clinical trials, selectively targeting the AR mdpi.comarvinas.com.

Addressing Resistance Mutations: New antiandrogens are being designed to be effective against pre-existing AR mutants that confer resistance to first-generation drugs. For example, mutations like W742C/L have been reported to cause this compound resistance oaepublish.comnih.gov. Understanding the structural basis of these mutations is crucial for designing inhibitors that can maintain efficacy researchgate.netcolab.wsresearchgate.net.

Tissue-Specific AR Modulators (SARMs): While some SARMs are in clinical development for conditions like muscle wasting and sarcopenia, their "selective" nature aims to provide clinical advantages by targeting specific tissues (e.g., muscle and bone) with fewer androgenic side effects on the prostate or hair growth mdpi.comcleancompetition.orgverupharma.comamegroups.org. Although this compound is not a SARM, the development of SARMs represents a broader effort to refine AR modulation for various therapeutic applications.

The pipeline for AR-targeted therapeutics is robust, with numerous molecules in various stages of development, including preclinical, Phase I, Phase II, and Phase III, indicating a strong focus on developing more selective and potent compounds with improved pharmacokinetic profiles mdpi.compharmaceutical-technology.com.

Advanced In Silico Modeling and Molecular Dynamics Simulations for Drug Optimization

Advanced in silico modeling and molecular dynamics (MD) simulations are increasingly vital tools in the rational design and optimization of drugs targeting the androgen receptor, including efforts to overcome this compound resistance. These computational methods provide detailed insights into ligand-receptor interactions and the structural basis of AR antagonism and agonism researchgate.netkuleuven.beresearchgate.netnih.govcardiosomatics.rumdpi.comnih.gov.

Key applications in this compound studies and AR drug optimization include:

Understanding Antagonism Mechanisms: MD simulations have been used to elucidate the structural basis for this compound's antagonist activity. For example, studies suggest that this compound antagonizes AR by accessing an additional binding pocket (B-site) adjacent to the hormone binding site, which displaces helix 12 and distorts the coactivator binding site, leading to transcriptional inactivation nih.govmdpi.com.

Investigating Resistance Mechanisms: Computational methods are instrumental in understanding how AR mutations convert antagonists into agonists or enable AR signaling recovery by alternative steroids. MD simulations have shown that the "closed" conformation of this compound is essential for its antagonist function and that specific residues, like W741, influence this conformation colab.wsresearchgate.net. Mutations such as W741C, W741L, T877A, and L701H have been analyzed to understand their impact on this compound's efficacy colab.wsresearchgate.net.

Structure-Based Drug Design (SBDD): Computational drug design, including virtual screening, pharmacophore modeling, and molecular docking, is employed to discover novel AR inhibitors kuleuven.bekuleuven.beresearchgate.netcardiosomatics.runih.gov. This involves screening large compound databases to identify potential hits that bind to the AR, including new allosteric sites or the DNA binding domain kuleuven.bekuleuven.be.

Predicting Binding Modes and Affinities: MD simulations, combined with molecular docking and free energy calculations (e.g., MM/GBSA), are used to analyze and compare the binding modes of novel compounds with the AR, identifying key interactions and driving forces like van der Waals interactions nih.gov. This allows for the prediction of binding affinities and the rational optimization of lead molecules kuleuven.becardiosomatics.runih.gov.

These computational approaches are powerful for developing new small molecule-based therapies, explaining the activity of small molecules, and designing improved antagonists by understanding structure-activity relationships (SAR) kuleuven.bekuleuven.beresearchgate.netcardiosomatics.ru.

Identification of Novel Biomarkers for Response and Resistance

The identification of novel biomarkers is crucial for predicting response to this compound and detecting the emergence of resistance, thereby enabling personalized treatment strategies. Current research focuses on both genomic and non-genomic markers, often utilizing liquid biopsy approaches for minimally invasive monitoring urologytimes.commdpi.come-century.usnih.govnih.gov.

Key areas of biomarker research include:

Genomic Alterations in AR: Mutations and amplifications in the AR gene are well-established mechanisms of this compound resistance oaepublish.comnih.govnih.govnd.edunih.gov. For instance, the W742C mutation in the AR has been identified as conferring resistance to this compound oaepublish.comnih.gov. Genomic profiling assays are being developed to detect these alterations, allowing clinicians to consider alternative therapeutic regimens nih.govwustl.edumdpi.comaacrjournals.org.

AR Splice Variants: The AR-V7 splice variant is a known predictive biomarker for resistance to AR-directed therapies, indicating that patients with this variant may benefit more from alternative treatments like taxane-based chemotherapy urologytimes.come-century.us. Liquid biopsy techniques, such as circulating tumor DNA (ctDNA) assays, are being refined for earlier and more sensitive detection of AR-V7 and other genomic alterations urologytimes.come-century.usnih.govwustl.edu.

MicroRNAs (miRNAs): Dysregulation of miRNA function is a putative mechanism of hormone therapy resistance acs.org. Studies have identified specific miRNAs, such as miR-216a and miR-15b-3p, that are involved in modulating this compound resistance in prostate cancer cells nih.govjcancer.org. MiR-15b-3p, for example, has been found to be significantly higher in prostate cancer tissues and may serve as a diagnostic biomarker and a potential therapeutic target jcancer.org.

Other Molecular Pathways: Research is also investigating other molecular pathways and factors contributing to this compound resistance, including the involvement of heat shock proteins, increased expression of DNA methyltransferases (DNMTs), and components of the Akt-mTOR pathway nih.gov. Interleukin 6 (IL-6) has also been implicated in this compound resistance and progression to CRPC nih.gov.

Liquid Biopsy for Real-time Monitoring: Liquid biopsies, which analyze circulating tumor cells (CTCs), ctDNA, extracellular vesicles (EVs), and secretome in body fluids, offer a non-invasive way to capture real-time genomic and transcriptomic changes in tumors urologytimes.commdpi.come-century.usnih.govwustl.edu. Assays like "EnhanceAR-Seq" are being developed to track genomic alterations in the AR enhancer, AR gene body, and other important genes to identify patients at high risk for resistance wustl.edu.

These advancements aim to provide more comprehensive and timely information for guiding personalized treatment decisions and improving patient outcomes in CRPC urologytimes.comnih.govnih.gov.

Integration of Multi-Omics Data in this compound Research

The integration of multi-omics data (genomics, transcriptomics, proteomics, metabolomics) is an emerging paradigm in this compound research, offering a comprehensive understanding of drug response and resistance mechanisms. This holistic approach moves beyond single-biomarker analysis to capture the complex interplay of molecular events within cancer cells and the tumor microenvironment nih.gov.

Key aspects of multi-omics integration include:

Comprehensive Molecular Profiling: By combining data from different omics layers, researchers can gain a deeper insight into the genetic landscape, gene expression patterns, protein activity, and metabolic changes associated with this compound treatment and the development of resistance nih.gov. For instance, whole genome expression profiling has been used to compare cellular responses to this compound in different prostate cancer cell lines, revealing distinct threshold responses and affected gene pathways nd.edu.

Identification of Novel Pathways and Targets: Multi-omics data can help identify previously unrecognized pathways or molecular targets that contribute to this compound resistance. For example, global transcriptomics has identified specific AR-driven genes, such as SGK1, TIPARP, and RASD1, that are markedly upregulated in this compound-resistant AR mutant cells, suggesting potential new avenues for therapeutic exploitation oncotarget.com.

Biomarker Discovery and Validation: Integrating multi-omics data facilitates the discovery and validation of more robust predictive and prognostic biomarkers. This can involve correlating genomic mutations with transcriptomic changes and proteomic profiles to identify signatures that reliably predict response or resistance to this compound nih.govnih.gov. For example, studies have identified hub genes associated with this compound resistance and constructed prognostic models based on gene expression profiles nih.gov.

Understanding Tumor Heterogeneity: Prostate cancer is a heterogeneous disease, and multi-omics approaches, especially through liquid biopsies, can provide insights into spatial and temporal tumor evolution, allowing for real-time monitoring of resistance mechanisms as they emerge e-century.usnih.gov. This can help in understanding how heterogeneous sub-populations contribute to this compound resistance researchgate.net.

Personalized Medicine: The ultimate goal of integrating multi-omics data is to enable highly personalized treatment strategies. By understanding the unique molecular profile of each patient's tumor, clinicians can make more informed decisions regarding the optimal use of this compound, combination therapies, or alternative treatments, particularly when resistance develops urologytimes.comnih.govwustl.edu.

The application of multi-omics data, particularly through research-grade liquid biopsy assays, holds significant clinical potential for enhancing prognostication and improving outcomes for patients treated with this compound and other AR-targeted therapies nih.gov.

Repurposing in Rare and Understudied Androgen-Sensitive Conditions

Beyond its primary use in prostate cancer, this compound is being investigated for repurposing in various rare and understudied androgen-sensitive conditions, leveraging its potent androgen receptor antagonism. This expands the therapeutic horizon for this compound and highlights its versatility as an AR modulator.

Conditions where this compound is being explored include:

Female Pattern Hair Loss and Hirsutism: this compound has garnered interest for its off-label use in improving female pattern hair loss and treating hirsutism, particularly in conditions like Polycystic Ovary Syndrome (PCOS) medrxiv.orgnih.govresearchgate.net. Its ability to control androgen effects at the tissue level makes it a valuable option for patients who may not respond to other therapies nih.gov.

Precocious Puberty: this compound has been used in rare forms of precocious puberty in cisgender boys, specifically familial male-limited precocious puberty, which is a GnRH-independent form driven by androgens. Studies have shown that this compound, sometimes in combination with anastrozole, can decrease growth rate and bone maturation rate in these patients medrxiv.orgnih.gov.

Gender-Affirming Hormone Therapy: this compound has gained popularity as an androgen blocker in gender-affirming hormone therapy for transfeminine individuals, particularly as an alternative to gonadotropin-releasing hormone (GnRH) analogs medrxiv.orgresearchgate.net. Research suggests it can promote breast development with potentially favorable properties like potent AR antagonism and negligible off-target effects compared to other anti-androgens researchgate.net.

Androgen Receptor-Positive Breast Cancer: While this compound is primarily known for prostate cancer, its potential in treating certain types of breast cancer, specifically androgen receptor (AR)-positive metastatic triple-negative breast cancer (mTNBC) and inflammatory breast cancer (IBC), is under investigation clinicaltrials.eumdpi.com. It has been explored in combination with other targeted therapies like abemaciclib or conventional chemotherapy (doxorubicin and docetaxel) to enhance efficacy clinicaltrials.eumdpi.com.

Salivary Gland Cancer: The androgen receptor is overexpressed in most patients with salivary duct carcinoma (SDC). Clinical trial data suggest the efficacy of androgen deprivation therapy with this compound, either alone or in combination with leuprolide, in recurrent or metastatic AR-overexpressing SDC mdpi.comaacrjournals.org.

These studies underscore the potential for this compound to address unmet medical needs in conditions where androgen signaling plays a significant pathological role, demonstrating its broader therapeutic utility beyond its established indications.