Dasatinib

Evolution from First-Generation TKIs

The clinical success of the first-generation TKI, imatinib, marked a turning point in targeted cancer therapy. nih.gov Approved in 2001 for the treatment of Philadelphia chromosome-positive (Ph+) CML, imatinib specifically targets the BCR-ABL fusion protein, a constitutively active tyrosine kinase central to the pathogenesis of CML. nih.govwikipedia.org Imatinib's introduction dramatically improved outcomes for patients with CML compared to conventional therapies. nih.govwikipedia.org However, despite its initial success, challenges emerged, primarily the development of resistance and intolerance in a significant subset of patients. nih.gov Resistance to imatinib often arises due to point mutations within the BCR-ABL kinase domain that impair imatinib binding. nih.govpatsnap.compnas.org

Rationale for Second-Generation TKI Development

The limitations of first-generation TKIs, particularly the emergence of resistance mutations in BCR-ABL and other kinases, provided a strong rationale for the development of second-generation TKIs. wikipedia.orgnih.govwikipedia.org The goal was to create more potent inhibitors capable of overcoming the most common resistance mechanisms observed with imatinib and potentially targeting a broader spectrum of kinases involved in cancer progression. nih.govpnas.org Second-generation TKIs were designed to bind to BCR-ABL with higher affinity and to be effective against many of the imatinib-resistant BCR-ABL mutants, with the notable exception of the T315I mutation. nih.govpnas.orgaacrjournals.org This effort aimed to provide alternative and more effective treatment options for patients who failed or were intolerant to imatinib. nih.gov

Discovery as BMS-354825

This compound was discovered and initially characterized as the compound BMS-354825 by researchers at Bristol-Myers Squibb. wikipedia.orgwikipedia.orgnih.govaacrjournals.org Its identification was a result of targeted research aimed at developing inhibitors with activity against key tyrosine kinases involved in cancer.

Early Preclinical Studies and Kinase Selectivity Profiling

Early preclinical studies of BMS-354825 demonstrated its potent inhibitory activity against BCR-ABL and members of the Src family kinases. wikipedia.orgnih.govaacrjournals.orgdrugbank.com Kinase selectivity profiling revealed that this compound inhibits a broader range of kinases compared to imatinib. aacrjournals.orgbiorxiv.org At nanomolar concentrations, this compound inhibits BCR-ABL, SRC family kinases (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. drugbank.com Studies showed that this compound binds to both the active and inactive conformations of the ABL kinase domain, a characteristic that contributes to its potency and activity against many imatinib-resistant mutants. aacrjournals.orgdrugbank.com

Preclinical pharmacokinetic studies in various animal models (mouse, rat, dog, and monkey) characterized the absorption, distribution, metabolism, and excretion of BMS-354825. These studies indicated that this compound shows intermediate clearance and distributes extensively. Oxidative metabolism was identified as the predominant clearance pathway. drugbank.comresearchgate.net

Data from Preclinical Pharmacokinetic Studies:

Based on data from Kamath et al. 2008. drugbank.comresearchgate.net

In vitro studies using BCR-ABL-positive cell lines demonstrated that this compound inhibited cell growth and increased apoptosis in a dose-dependent manner, correlating with diminished levels of phosphorylated BCR-ABL and phospho-CrkL. drugbank.comfrontiersin.org Animal models bearing human tumor xenografts showed that oral administration of this compound led to dose-dependent inhibition of tumoral phospho-BCR-ABL/phospho-SRC, which correlated with plasma concentrations of this compound. frontiersin.orgaacrjournals.org

Activity in Xenograft Models

Preclinical studies utilizing xenograft models were instrumental in evaluating the antitumor activity of this compound. This compound demonstrated selective activity in several tumor models within the Pediatric Preclinical Testing Program. nih.gov

In studies evaluating this compound's antitumor effects in nude mice bearing tumors derived from the CML cell line K562, treatment with this compound induced partial regression of tumors after one cycle and complete regression by the end of treatment, without observed toxic side effects. acs.org

This compound's efficacy has also been investigated in xenograft models of solid tumors. In a study using colorectal cancer (CRC) cell lines and patient-derived tumor explants (PDX) models, this compound showed significant anti-proliferative activity in a subset of CRC cell lines in vitro, particularly those with increased baseline Src expression. plos.org In 17 CRC explants grown in a xenograft mouse model, 2 showed sensitivity to this compound, with tumor growth inhibition (TGI) of 50% or more considered sensitive. plos.org The antitumor effects observed in sensitive CRC cell lines were linked to G1 cell cycle arrest. plos.org

Studies in ovarian cancer xenograft models (A2780 and HO8910) in nude mice assessed the antitumor effect of this compound alone and in combination with paclitaxel. This compound treatment alone inhibited tumor growth by 43.2% in A2780 xenografts and 34.0% in HO8910 xenografts. spandidos-publications.com

This compound has also shown activity in patient-derived xenograft (PDX) models of lung cancer. In SCID mice with tumors highly expressing LIMK1, this compound (30 mg/kg) significantly inhibited tumor growth without affecting body weight. frontiersin.org This anti-tumor activity was found to be mediated by LIMK1 inhibition. frontiersin.org

Furthermore, this compound has been shown to induce regression in GIST-derived xenograft models containing secondary mutations that confer resistance to other tyrosine kinase inhibitors like imatinib and sunitinib. nih.gov

Here is a summary of this compound activity in select xenograft models:

Initial Pharmacokinetic Assessments Guiding Development

Initial pharmacokinetic assessments played a crucial role in guiding the development of this compound. Following oral administration, this compound was generally absorbed rapidly. fda.gov In single-dose studies in rats and monkeys, and a repeat-dose study in monkeys, the time to maximum plasma concentration (Tmax) was typically between 1 and 2 hours. fda.gov However, larger variations in Tmax (2-8 hours) were reported in repeat-dose studies in rats. fda.gov In humans, maximum plasma concentrations are generally observed between 0.5 and 6 hours after oral administration. frontiersin.orgfda.gov

This compound exhibits dose-proportional increases in the area under the curve (AUC) and linear elimination characteristics over a dose range of 15–240 mg/day. researchgate.net The mean terminal half-life of this compound is reported to be between 3 and 5 hours. researchgate.net Preclinical studies showed oral bioavailability values ranging from 45% to 51% in mice, while other experiments across various species indicated values between 14% and 34%. frontiersin.orgresearchgate.net Specifically, bioavailability was reported as 14% and 17% in mice, 27% in rats, 34% in dogs, and 15.2% in monkeys. researchgate.net

The solubility of this compound is significantly influenced by gastric pH, which can impact its absorption from the gastrointestinal tract. semanticscholar.orgresearchgate.net At approximately pH 1, the solubility is high (49.6 mg/ml), dropping significantly to 3.62 mg/ml at pH 3.64 and becoming practically insoluble at higher pH values. semanticscholar.org This pH-dependent solubility is an important factor to consider, as gastric pH can vary and be influenced by co-administered medications. semanticscholar.orgresearchgate.net

Initial assessments indicated that this compound has an immunosuppressive potential, partly attributed to its ability to inhibit the LCK kinase involved in T-cell signaling, which was shown to reduce T-cell proliferation. fda.gov

pH-Dependent Absorption and Clinical Implications

A critical factor influencing this compound absorption is gastric pH frontiersin.orgsemanticscholar.org. This compound is classified as a weak base drug with pKa values of 3.1, 6.8, and 10.8 frontiersin.orgmdpi.com. It exhibits higher solubility in acidic environments and tends to precipitate in the small intestine frontiersin.orgmdpi.com. Studies have shown that elevated gastric pH, particularly in the range of 4.0–6.0, can significantly reduce this compound solubility frontiersin.org.

The pH-dependent solubility has significant clinical implications, as co-administration of agents that increase gastric pH can substantially impact this compound's oral bioavailability frontiersin.orgsemanticscholar.org. Proton pump inhibitors (PPIs), H2-receptor antagonists (H2RAs), and antacids are known to increase gastric pH and have been shown to decrease this compound's Cmax and AUC frontiersin.orgfda.gov. For instance, co-administration with ketoconazole, a strong CYP3A4 inhibitor that also affects pH, increased this compound Cmax and AUC significantly frontiersin.org. Conversely, agents that reduce gastric acid can lead to a substantial decrease in this compound exposure fda.gov. A study showed that administering a single dose of this compound 3 hours after famotidine (an H2RA) resulted in a significant decrease in this compound AUC and Cmax compared to administration without an H2RA fda.gov.

Bioavailability Variability

The oral bioavailability of this compound has been reported to be relatively low in preclinical studies, ranging from 14% to 51% frontiersin.org. The observed high inter- and intra-subject variability in this compound exposure is attributed, in part, to factors influencing absorption, including gastric pH and potentially other gastrointestinal factors like gastric emptying and fluid volume mdpi.comonclive.com. While a high-fat meal can slightly increase the mean AUC of this compound, this change is generally not considered clinically significant frontiersin.orgsemanticscholar.org. Novel formulations, such as amorphous solid dispersion (ASD), have been investigated to potentially improve bioavailability and reduce variability by maintaining increased solubility across a wider pH range onclive.comnih.gov. Studies with a this compound ASD formulation (XS004) have shown improved gastrointestinal absorption and bioavailability with significantly reduced intra- and intersubject variability in plasma concentrations compared to the original crystalline formulation onclive.comnih.gov.

Hepatic Metabolism (e.g., CYP3A4, CYP1A1, CYP1B1, FMO3 involvement)

The primary enzyme responsible for this compound metabolism is cytochrome P450 (CYP) 3A4 frontiersin.orgdrugbank.commdpi.comfda.govpharmgkb.orgnih.govuniversiteitleiden.nlscispace.com. CYP3A4 is involved in the formation of several metabolites, including the active metabolite M4 and the hydroxylated metabolites M20 and M24 drugbank.commdpi.compharmgkb.org. Other enzymes also play a role in this compound metabolism. Flavin-containing monooxygenase 3 (FMO3) is primarily involved in the formation of the M5 metabolite (this compound n-oxide) drugbank.compharmgkb.orguniversiteitleiden.nlscispace.comresearchgate.net. Uridine diphosphate-glucuronosyltransferase (UGT) enzymes are also implicated in the formation of this compound metabolites, including a glucuronide metabolite known as M8 drugbank.compharmgkb.orguniversiteitleiden.nl. In vitro data suggest that CYP1A1 and CYP1B1 are also capable of metabolizing this compound, although their in vivo relevance requires further investigation pharmgkb.orguniversiteitleiden.nlscispace.comresearchgate.net.

Metabolite Identification (e.g., M4, M5, M6, M20, M24, M8)

Several circulating metabolites of this compound have been identified. The primary oxidative metabolites include M4 (N-dealkylated), M5 (N-oxide), M6 (acid metabolite), M20 (hydroxylated), and M24 (hydroxylated) drugbank.commdpi.compharmgkb.org. M4 is considered the primary active metabolite, exhibiting in vitro antiproliferative activity similar to that of this compound, although it represents a relatively small fraction (approximately 5%) of the this compound AUC frontiersin.orgdrugbank.commdpi.com. M20 and M24 also have reported potency mdpi.com. M5 and M6 are considered minor circulating metabolites and are significantly less active than this compound drugbank.commdpi.com. A glucuronide metabolite, M8, is also formed pharmgkb.org.

Excretion Routes (Fecal vs. Renal)

This compound is primarily eliminated from the body via the feces semanticscholar.orgdrugbank.comfda.govnih.govuniversiteitleiden.nl. Following oral administration of radiolabeled this compound, approximately 85% of the administered radioactivity was recovered in the feces within 10 days drugbank.comfda.gov. Unchanged this compound accounts for a small percentage of the dose excreted in feces (around 19%), with the majority being metabolites drugbank.comfda.gov. Renal excretion plays a minor role, with only about 4% of the administered radioactivity recovered in the urine drugbank.comfda.gov. Unchanged this compound in urine accounts for less than 1% of the dose drugbank.comfda.gov.

Relationship between Plasma Concentration and Target Inhibition (e.g., pSRC inhibition)

Studies have investigated the relationship between this compound plasma concentration and the inhibition of its molecular targets, such as phosphorylated SRC (pSRC). In phase I studies, pSRC inhibition in peripheral blood mononuclear cells (PBMCs) appeared to be directly correlated with this compound plasma concentration. ascopubs.org Maximal inhibition was typically achieved around 2.5 hours post-dosing. ascopubs.org Based on pharmacokinetic-pharmacodynamic modeling, the estimated EC50 (the plasma concentration required to achieve 50% inhibition of pSRC) was determined to be 14.4 ng/mL. ascopubs.org This suggests that SRC family kinase activity is substantially inhibited at the this compound exposures achieved in these studies. ascopubs.org Preclinical studies, both in vivo and in vitro, have also suggested a correlation between kinase inhibition efficacy and this compound exposure. researchgate.net In BCR-ABL-positive cell lines, increasing this compound concentrations led to considerable reductions in phospho-BCR-ABL/phospho-CrkL (p-CrkL) levels and increased apoptosis. researchgate.net Similar findings were observed in SRC-expressing cells. researchgate.net this compound has demonstrated potent Src inhibitory activity in CML progenitors, inhibiting both BCR-ABL dependent and independent Src activity. nih.gov

Exposure-Response Relationships for Efficacy and Safety

Research has revealed a correlation between this compound exposure and clinical response. dovepress.com However, significant interpatient variability in this compound exposure exists, with maximum plasma drug concentration (Cmax) showing 70–80% variability and area under the plasma concentration-time curve (AUC) showing 40–54% variability. frontiersin.org This variability can lead to some patients experiencing toxicity due to high exposure and others having suboptimal efficacy due to low exposure. dovepress.com

Studies have explored the relationship between specific pharmacokinetic parameters and clinical outcomes. For instance, in one analysis, the efficacy (measured by BCR-ABL expression at 1 month) was not significantly correlated with AUC, Cmax, AUC/IC50, or Cmax/IC50, but it did show a significant correlation with the time above IC50 (TAIC50). ashpublications.org The reduction rate at 1 month was also significantly correlated with TAIC50. ashpublications.org Patients with a TAIC50 of more than 12 hours showed a higher rate of achieving major molecular response (MMR) at 3 months compared to those with a TAIC50 of less than 12 hours. ashpublications.org Another study found a robust correlation between peak concentration (Cmax) and clinical response (MMR and deep molecular response (DMR)). dovepress.com Patients with a Cmax > 51.85 ng/mL were more likely to achieve MMR, and those with a Cmax exceeding 112.5 ng/mL had a higher probability of attaining DMR. dovepress.com

Regarding safety, trough concentrations (Cmin) have been closely associated with the onset of pleural effusion. dovepress.comresearchgate.netdovepress.com A Cmin > 2.48 ng/mL was linked to an increased risk of this adverse event. dovepress.com Exposure-safety response analyses have described the relationship between this compound Cmin and the occurrence of pleural effusion. researchgate.net Higher this compound exposure also correlates strongly with toxicity. researchgate.net

Here is a summary of some observed exposure-response relationships:

Therapeutic Drug Monitoring and Individualized Medicine Applications

Therapeutic drug monitoring (TDM) is increasingly being explored as a practical tool to facilitate individualized medicine for patients receiving targeted therapies like this compound. frontiersin.orgfrontiersin.orgdovepress.com Despite the high pharmacokinetic variability observed with this compound, fixed dosing remains the standard approach. frontiersin.orgfrontiersin.org However, evidence suggests that TDM could potentially optimize a patient's drug regimen based on drug concentrations in biological fluids. frontiersin.org TDM may help patients maintain treatment response while minimizing adverse events, potentially leading to improved long-term survival. frontiersin.org

Studies have investigated the application of TDM for optimizing this compound dosage, particularly in patients with chronic-phase CML. dovepress.comdovepress.com Analysis has revealed a robust correlation between peak concentration (Cmax) and clinical response (MMR and DMR), as well as an association between trough concentration (Cmin) and the occurrence of pleural effusion. dovepress.com These findings suggest that TDM-based dose optimization could lead to beneficial clinical outcomes. dovepress.com For instance, dose reduction based on this compound concentrations has been successfully implemented in some patients without loss of deep molecular response. dovepress.com

Interactions with Gastric pH Modifying Agents (Antacids, H2-receptor blockers, Proton Pump Inhibitors)

The solubility of this compound is pH-dependent, decreasing significantly as pH increases above 4.0. researchgate.net Consequently, agents that modify gastric pH can impact this compound absorption and systemic exposure. researchgate.netashpublications.orgresearchgate.net

Concomitant use of this compound with agents that provide prolonged gastric acid suppression, such as H2-receptor antagonists and proton pump inhibitors (PPIs), is generally not recommended. researchgate.netashpublications.orgdrugs.comdrugs.com Studies have shown that administration of the H2-receptor antagonist famotidine before this compound dosing can significantly reduce this compound exposure. researchgate.netashpublications.orgdrugs.comdrugs.comthd.org.tr For example, administration of this compound 10 hours after famotidine was associated with an approximately 60% reduction in this compound peak plasma concentration (Cmax) and systemic exposure (AUC). drugs.comdrugs.com Similarly, administration of this compound following omeprazole (a PPI) also resulted in a reduction in this compound Cmax and AUC. drugs.comdrugs.com In Japanese leukemia patients, the dose-adjusted AUC of this compound was significantly lower in those administered an H2RA or PPI compared to those not receiving acid suppressants. researchgate.net

Unlike H2-receptor antagonists and PPIs, this compound may be administered with acid-neutralizing antacids, provided the doses are separated in time. researchgate.net However, simultaneous administration of this compound with antacids should be avoided. fda.gov When a magnesium-aluminum-based antacid was coadministered with this compound, this compound exposure was reduced by 55%-58%. ashpublications.orgthd.org.tr If antacid therapy is necessary, the antacid dose should be administered at least 2 hours prior to or 2 hours after the this compound dose. fda.govdrugs.comdrugs.com

Interactions with CYP3A4 Inducers and Inhibitors

This compound is a substrate of CYP3A4, and its plasma concentrations can be significantly altered by concomitant administration of CYP3A4 inducers or inhibitors. fda.govcancercareontario.cauptodateonline.ir

Concomitant use of this compound with strong CYP3A4 inhibitors should generally be avoided as they can increase this compound exposure by decreasing its metabolism. fda.govcancercareontario.cauptodateonline.ir Examples of strong CYP3A4 inhibitors include ketoconazole, itraconazole, erythromycin, clarithromycin, and certain protease inhibitors. fda.govcancercareontario.cauptodateonline.ir In a study, coadministration of this compound with ketoconazole increased the this compound Cmax and AUC by four- and five-fold, respectively. fda.gov If concomitant administration with a potent CYP3A4 inhibitor cannot be avoided, close monitoring for toxicity and a this compound dose reduction should be considered. fda.govcancercareontario.cauptodateonline.ir

Conversely, drugs that induce CYP3A4 activity can decrease this compound plasma concentrations by increasing its metabolism. fda.govcancercareontario.cauptodateonline.ir Strong CYP3A4 inducers include agents such as rifampin, phenytoin, carbamazepine, phenobarbital, and dexamethasone. fda.govcancercareontario.cauptodateonline.ir Concomitant administration of the CYP3A4 inducer rifampicin has been shown to lead to an 80% reduction in this compound exposure. fda.govthd.org.tr St. John's wort, a herbal supplement, is also a CYP3A4 inducer and may unpredictably decrease this compound plasma concentrations; therefore, it should be avoided in patients receiving this compound. fda.govcancercareontario.cauptodateonline.ir If this compound must be administered with a CYP3A4 inducer, a dose increase in this compound should be considered, along with careful monitoring. fda.govuptodateonline.ir

This compound can also affect the exposure of other drugs that are substrates of CYP3A4. cancercareontario.ca For example, the coingestion of this compound with simvastatin, a CYP3A4 substrate, resulted in a 20% increased exposure to simvastatin. thd.org.tr Caution is advised when co-administering this compound with CYP3A4 substrates that have a narrow therapeutic index. cancercareontario.ca

BCR-ABL1 Overexpression

Altered Transcriptional Regulation

Altered transcriptional regulation can contribute to dasatinib resistance. Studies have investigated gene expression profiles in patients treated with this compound to identify pathways associated with resistance. researchgate.net For instance, altered expression of non-coding RNAs transcribed from introns of genes involved in the regulation of transcription, signal transduction, and apoptosis has been observed in the context of this compound resistance. researchgate.net Transcriptional plasticity, such as the upregulation of alternative pathways like WNT signaling, has been suggested as a mechanism for acquired this compound resistance in some cell types. aacrjournals.org Additionally, altered transcription factors or chromatin regulators can affect a tumor's response to treatment and contribute to resistance. frontiersin.org

Myristoyl Domain Mutations

While this compound primarily targets the ATP-binding site of BCR-ABL1, mutations in the myristoyl-binding site have been reported to confer resistance to other ABL inhibitors like asciminib, which acts allosterically by binding to this domain. iiarjournals.orgnih.gov Although directly linked to asciminib, alterations in this region could potentially influence the conformation and function of BCR-ABL1, indirectly impacting this compound binding or downstream signaling, though this requires further investigation specific to this compound resistance.

Activation of Alternative Signaling Pathways

Activation of alternative signaling pathways is a key mechanism of BCR-ABL1-independent resistance to this compound. iiarjournals.orgnih.govnih.gov These pathways can compensate for the inhibited BCR-ABL1 signaling, promoting cell survival and proliferation. iiarjournals.org

PI3K/AKT/mTOR Pathway Activation

The PI3K/AKT/mTOR pathway is a critical signaling cascade involved in cell growth, survival, and proliferation, and its dysregulation is frequently associated with drug resistance in various cancers. nih.govspandidos-publications.comguidetopharmacology.org Activation of the PI3K/AKT/mTOR pathway has been implicated in this compound resistance. nih.govspandidos-publications.comciteab.com Studies in this compound-resistant cells have shown sustained activation of the AKT/mTOR pathway. oncotarget.com While this compound can suppress the PI3K/AKT/mTOR pathway in some cancer cell types, its activation in others can compromise its efficacy as an anti-cancer drug. nih.govoup.com this compound-resistant cells may exhibit increased levels of phosphorylated AKT and mTOR. nih.gov This pathway's activation can provide survival signals that circumvent the effects of BCR-ABL1 inhibition by this compound. iiarjournals.org

JAK/STAT Pathway Activation

The JAK/STAT pathway is another signaling route that can contribute to BCR-ABL1-independent this compound resistance. researchgate.netresearchgate.net Aberrant activation of STAT-3, a downstream component of the JAK pathway, can preserve CML cells even when BCR-ABL1 activity is suppressed by TKIs like this compound. iiarjournals.org In some contexts of this compound resistance, particularly in KIT-mutant acute myeloid leukemia cells with KIT downregulation, increased ERK signaling has been observed, while STAT3 levels were decreased. nih.gov However, other research indicates that altered Jak-STAT3 binding can activate STAT3, potentially contributing to resistance to Src inhibition by this compound. oup.com

RAS/MAPK/ERK Pathway Activation

The RAS/MAPK/ERK pathway plays a crucial role in regulating cell proliferation and survival. plos.org Activation of the RAS/MAPK/ERK pathway can mediate BCR-ABL1-independent resistance to this compound. iiarjournals.orgnih.govresearchgate.net Increased activation of the RAS pathway, potentially through mechanisms independent of BCR-ABL1 signaling, can lead to TKI resistance. mdpi.com this compound-resistant cells have shown increased levels of phosphorylated ERK1/2. nih.gov This pathway can be upregulated to compensate when other pathways, such as the PI3K/AKT pathway, are inhibited. oncotarget.com Inhibition of components within the MAPK/ERK pathway, such as MEK1/2, has been shown to overcome this compound resistance in some contexts. nih.gov

Changes in Drug Transporter Activity

Alterations in the activity and expression of drug transporters, particularly ATP-Binding Cassette (ABC) transporters, play a significant role in the development of resistance to this compound. pensoft.netmdpi.com These transporters can reduce the intracellular concentration of the drug by actively pumping it out of the cell. pensoft.netpharmacologyeducation.org

ATP-Binding Cassette (ABC) Transporters (e.g., ABCB1, ABCG2, ABCC6)

ABCC6 (Multidrug Resistance-Associated Protein 6) has also been identified as playing a significant role in the transport of this compound. plos.org Studies have suggested that this compound is likely a substrate of ABCC6, and its overexpression may contribute to this compound resistance in vitro. plos.org Chemical inhibition of ABCC6 has been shown to increase the efficacy of this compound in BCR-ABL1+ cell lines by reducing this compound efflux. researchgate.net Increased expression of ABCC6 mRNA has been observed during the in vitro development of resistance to TKIs, including this compound. plos.org This suggests a concerted increase in ABCB1 and ABCC6 expression during the development of resistance in some cell models. plos.org

The involvement of ABC transporters in TKI resistance is well-documented, with ABCB1 and ABCG2 being extensively characterized for their role in multidrug resistance. upgx.eu this compound has been documented as a competitive or high-affinity substrate of ABCG2 and interacts with its substrate-binding sites. mdpi.com Some studies also show that ABCB1 confers resistance to this compound. mdpi.com

Combination with Valproic Acid in Acute Myeloid Leukemia (AML)

The combination of this compound and Valproic Acid (VPA), an anti-epileptic drug also known for its activity as a class I histone deacetylase inhibitor, has been investigated for its anti-leukemic effects in acute myeloid leukemia (AML) cells. This combination has shown potent synergistic inhibitory effects. plos.orgnih.govaacrjournals.orgnih.gov

Acceleration of Cell Death and Differentiation Capacity Regulation

Combined treatment with this compound and VPA has been observed to accelerate cell death in AML cells. This effect is associated with the induction of G1 phase cell cycle arrest and apoptosis. plos.orgnih.govaacrjournals.orgnih.gov The apoptotic process involves the cleavage of poly (ADP-ribose) polymerase (PARP), caspase-3, caspase-7, and caspase-9, indicating a caspase-dependent pathway of cell death. plos.orgnih.govaacrjournals.orgnih.gov Furthermore, the combination of this compound and VPA has a more powerful effect on the differentiation capacity of AML cells compared to either drug alone. plos.orgnih.govaacrjournals.orgnih.govresearchgate.net This enhanced differentiation capacity is sufficiently strong to promote significant AML cell death through G1 cell cycle arrest and caspase-dependent apoptosis. plos.orgnih.govaacrjournals.orgnih.govresearchgate.net

Involvement of MEK/ERK and p38 MAPK Inhibition

Studies have indicated that MEK/ERK and p38 MAPK inhibitors efficiently inhibit this compound/VPA-induced apoptosis in AML cells. plos.orgnih.govaacrjournals.orgnih.gov This suggests that MEK/ERK and p38 MAPK pathways act as upstream regulators controlling the apoptosis induced by the this compound and VPA combination. plos.orgnih.govaacrjournals.orgnih.govresearchgate.net The regulation of cell differentiation capacity by the co-treatment is also understood to contribute to AML cell death, mediated through these pathways. plos.orgnih.govaacrjournals.orgnih.govresearchgate.net

Combination with MEK Inhibitors to Overcome Resistance

Combining this compound with MEK inhibitors has been explored as a strategy to overcome resistance to targeted therapies, including resistance to SRC inhibitors like this compound itself or other agents like imatinib. Research suggests that the combination of a SRC inhibitor (such as this compound or bosutinib) and a MEK inhibitor (such as trametinib or selumetinib) can exhibit synergistic inhibitory effects on cell proliferation in various cancer cell lines, including non-small-cell lung cancer (NSCLC) and erlotinib-resistant NSCLC. frontiersin.orgoncotarget.combiorxiv.org This combination has shown strong pro-apoptotic effects in CML cell lines resistant to imatinib due to various mechanisms, including mutations in the BCR-ABL1 kinase domain, overexpression of BCR-ABL1, or overexpression of Lyn. researchgate.net Furthermore, the combination of this compound and MEK inhibitors may be effective in treating CML cells harboring secondary BCR-ABL1 point mutations. researchgate.net Studies in thyroid cancer cells resistant to this compound have also shown that the combination of this compound and MEK1/2 inhibition resulted in synergistic growth inhibition and induction of apoptosis. oncotarget.com This suggests that sustained activation of the MAP kinase pathway can mediate resistance to SRC inhibitors like this compound, and its inhibition in combination with this compound can be an effective strategy. oncotarget.com

Combination with Dendritic Cell Vaccine in Metastatic Breast Cancer

The combination of this compound with dendritic cell (DC) vaccines has shown promising synergistic anti-tumor effects in models of metastatic breast cancer. nih.govresearchgate.netnih.gov While single treatment with either this compound or a DC vaccine may show limited efficacy, their combination has resulted in a significant decrease in tumor volume and a reduction in the number of metastatic lung nodules in mouse models. nih.govresearchgate.netnih.gov This combined approach has also led to increased survival time compared to single treatments. nih.govnih.gov The synergistic therapeutic effect appears to be largely dependent on the expansion and recruitment of CD8+ T cells and Natural Killer (NK) cells to the tumor microenvironment. nih.govresearchgate.netnih.gov this compound is thought to contribute by improving the expansion and recruitment of these immune cells and potentially enhancing the immunostimulatory capacity of DCs, while also reducing immunoregulatory cell populations. nih.govresearchgate.netbmj.combahrainmedicalbulletin.com

Targeting Modulators of this compound Sensitivity (e.g., CBP)

Research has identified modulators of this compound sensitivity, such as CREB-binding protein (CBP), which can be targeted in combination with this compound to enhance its efficacy. In pre-BCR+ acute lymphoblastic leukemia (ALL), depletion of the transcriptional co-activator CBP has been shown to increase this compound sensitivity. nih.govnih.govresearchgate.net This increased sensitivity is linked to the downregulation of transcription of the pre-BCR signaling pathway, which is associated with this compound sensitivity. nih.govnih.gov Acquired resistance to this compound in these cells can involve the upregulation of alternative pathways, including the WNT pathway. nih.gov Small molecules that disrupt the interaction of CBP with β-catenin have shown promising preclinical efficacy in combination with this compound, highlighting the role of CBP in modulating this compound sensitivity through bypass pathways like WNT signaling. nih.govnih.gov Targeting CBP represents a potential therapeutic approach to ameliorate this compound sensitivity and prevent resistance in certain ALL subtypes. nih.govnih.gov

Strategies to Overcome Drug Efflux Mechanisms

Drug efflux transporters, particularly those belonging to the ATP-binding cassette (ABC) transporter family, play a crucial role in the development of multidrug resistance (MDR) by actively pumping drugs out of cancer cells, thereby reducing their intracellular concentration and limiting their efficacy. nih.govmdpi.commdpi.com this compound has been identified as a substrate for several ABC transporters, including ABCB1 (P-glycoprotein/MDR1), ABCG2 (Breast Cancer Resistance Protein/BCRP), and ABCC6 (MRP6). frontiersin.orgnih.govnih.govpensoft.net Overexpression of these transporters can lead to reduced intracellular levels of this compound and increased resistance in various cancer cell lines, including leukemia cells. frontiersin.orgpensoft.net

Strategies to overcome drug efflux mechanisms mediated by ABC transporters often involve the co-administration of inhibitors that can block the transporter activity, thereby increasing the intracellular accumulation of this compound. For instance, studies have shown that this compound is a high-affinity substrate of ABCG2, and this transporter can mediate effective resistance to the compound in cancer cells. nih.govnih.gov Similarly, ABCB1 has also been shown to interact with this compound and contribute to resistance. nih.govnih.gov The central nervous system (CNS) delivery of this compound is notably restricted by both P-gp and BCRP, suggesting a synergistic activity of these transporters in limiting its brain penetration. frontiersin.orgnih.gov

Inhibition of these efflux pumps can enhance this compound's effectiveness. For example, co-administration of cyclosporine, a calcineurin inhibitor, has been shown to increase the peak concentration and area under the curve of this compound in mice, contributing to enhanced disease control, likely due to competitive inhibition of drug efflux and metabolism processes. nih.gov Another study demonstrated that this compound could reverse P-gp-mediated MDR in breast cancer cells by downregulating P-gp expression, potentially through inhibiting the activation of the ERK signaling pathway. nih.gov

Inhibition of Alternative Signaling Pathways

Resistance to this compound can also arise from the activation of alternative signaling pathways that compensate for the inhibition of BCR-ABL and other this compound targets. dovepress.complos.org These pathways can promote cell survival and proliferation, bypassing the therapeutic effects of this compound. Identifying and simultaneously inhibiting these alternative pathways is a key strategy to restore or enhance this compound sensitivity.

Several alternative pathways have been implicated in this compound resistance, including the PI3K/Akt/mTOR, JAK/STAT, and RAS/MAPK pathways. nih.govnih.govdovepress.com For example, activation of the PI3K/Akt/mTOR pathway has been shown to be important in imatinib resistance and can also contribute to resistance to second-generation TKIs like this compound. nih.govdovepress.com Inhibiting components of this pathway, such as mTOR, in combination with this compound has shown synergistic activity in preclinical models. nih.govoncotarget.com

Upregulation of alternative pathways like WNT has also been observed in acquired resistance to this compound in pre-BCR+ acute lymphoblastic leukemia. aacrjournals.org Small molecules that disrupt interactions within these alternative pathways have shown promising preclinical efficacy in combination with this compound. aacrjournals.org Furthermore, activation of ERK1/2 by MOS and TPL2 has been linked to BCR::ABL1-independent this compound resistance in chronic myeloid leukemia cells. nih.gov

In some contexts, such as glioblastoma, this compound's activity against Src family kinases and focal adhesion kinase (FAK), which are involved in cell migration and invasion, suggests its potential in overcoming resistance associated with epithelial-mesenchymal transition (EMT) and targeting the more drug-resistant mesenchymal cell subpopulation. virtualtrials.orgoncotarget.com Combining this compound with inhibitors targeting these alternative or compensatory pathways can lead to enhanced anti-tumor effects and overcome resistance.

Co-administration of ABCG2 Inhibitors

Given that ABCG2 is a significant efflux transporter for this compound, co-administration of specific ABCG2 inhibitors represents a direct strategy to increase intracellular this compound concentrations and enhance its efficacy, particularly in resistant cells or in anatomical compartments where efflux is prominent, such as the CNS. frontiersin.orgaacrjournals.orgnih.govnih.govpensoft.netnih.govnih.gov

Studies have demonstrated that this compound is a high-affinity substrate of ABCG2, and its efflux by this transporter contributes to resistance. nih.govnih.gov Inhibition of ABCG2 can lead to increased intracellular accumulation of this compound and enhanced cytotoxicity in ABCG2-overexpressing cells. frontiersin.orgpensoft.net

Solid Tumors Researchresearchgate.netnih.govmorrisanimalfoundation.orgresearchgate.net

Preclinical studies have shown that this compound can act as a cytostatic agent in various solid tumor cell lines, inhibiting proliferation, invasion, and metastasis nih.gov. Emerging clinical data from Phase 1 and 2 trials support these observations, demonstrating activity in a range of solid tumors, both as a single agent and in combination therapies nih.gov.

Breast Cancer (Preclinical and Early Clinical Studies)nih.govresearchgate.net

Preclinical studies in breast cancer cell lines, particularly those with a basal-like phenotype or classified as triple-negative breast cancer (TNBC), have indicated sensitivity to this compound aacrjournals.orgmdpi.comresearchgate.nettandfonline.com. This compound has shown growth inhibition of breast cancer cells and synergistic or additive activity when combined with chemotherapy in preclinical TNBC models aacrjournals.orgresearchgate.net.

However, clinical trials evaluating single-agent this compound in unselected patients with advanced or metastatic TNBC have shown limited activity aacrjournals.orgmdpi.comresearchgate.net. For instance, a Phase 2 study in patients with locally advanced or metastatic TNBC reported limited single-agent activity aacrjournals.org.

Data from a Phase 2 study in advanced TNBC patients who were evaluable for response included:

(Based on data from a Phase 2 study in advanced TNBC researchgate.net)

Research is ongoing to identify specific molecular markers that might predict response to this compound in breast cancer and to explore its potential in combination therapies mdpi.comresearchgate.nettandfonline.com. Preclinical studies suggest that combining this compound with a c-Met inhibitor may be a rational strategy to overcome acquired resistance in TNBC mdpi.com. A Phase II study is currently recruiting to evaluate the efficacy and safety of combined treatment of this compound, quercetin, and chemotherapy in metastatic TNBC patients who have progressed during or following chemotherapy careacross.com.

Hepatocellular Carcinomaresearchgate.net

This compound has been investigated for its effects on hepatocellular carcinoma (HCC) cell growth. Studies have shown that this compound can inhibit the proliferation of certain HCC cell lines by targeting SFKs oup.comresearchgate.net. For example, this compound potently inhibited the proliferation of SNU-449 cells oup.comnih.gov.

However, the efficacy of this compound as a single agent in HCC has been compromised by mechanisms such as the activation of the Akt/mTOR signaling pathway in some cell lines oup.comnih.gov. For instance, while this compound inhibited Src phosphorylation in SK-Hep-1 cells, it also activated the PDK1/Akt/mTOR pathway, limiting its anti-proliferative effect oup.comnih.gov.

Combinations of this compound with other agents are also being explored in HCC. A study evaluating the synergistic effect of this compound and phenethyl isothiocyanate (PEITC) on HCC demonstrated that the combination showed improved synergistic cytotoxicity towards HepG2 cells in vitro and reduced metastatic potential in vivo mdpi.com.

Tongue Squamous Cell Carcinomaresearchgate.net

Research into tongue squamous cell carcinoma (TSCC) has identified SFKs as significant contributors to tyrosine phosphorylation patterns in TSCC cell lines biorxiv.orgresearchgate.net. Inhibition of SFK activity with this compound has been shown to impair TSCC cell viability in both 2D cell culture and 3D soft agar colony formation assays biorxiv.orgresearchgate.net.

High-throughput drug combination screens have identified glucocorticoids as potential candidates for synergistic activity with this compound against TSCC cell viability biorxiv.orgresearchgate.net. Combination treatment with this compound and dexamethasone has shown strong synergistic effects, impacting Src and p130Cas phosphorylation and leading to reduced p130Cas expression biorxiv.orgresearchgate.net. This combination also induced G1 cell cycle arrest, increased senescence, and enhanced autophagy in TSCC cells biorxiv.orgresearchgate.net. Additionally, dexamethasone suppressed the phosphorylation of the MET kinase and its substrate Gab1, identifying them as new glucocorticoid targets biorxiv.orgresearchgate.net.

Lung Cancermdpi.com

This compound has been tested in clinical trials for non-small cell lung cancer (NSCLC) as a single agent and in combination with other therapies researchgate.netplos.orgspandidos-publications.com. While single-agent this compound has shown modest clinical efficacy in unselected NSCLC patients, marked activity or stable disease was observed in a subset of patients bmj.comspandidos-publications.com.

Preclinical studies in lung cancer cell lines have shown that this compound can inhibit growth and induce apoptosis, particularly in EGFR-mutant cells researchgate.netnih.gov. However, in cell lines lacking activating EGFR mutations, this compound treatment alone had minimal effect, primarily causing growth arrest rather than apoptosis plos.org.

Data from a meta-analysis of clinical trials in lung cancer involving this compound showed varying treatment responses:

(Based on data from a meta-analysis of clinical trials spandidos-publications.com)

Melanoma and Sarcomatandfonline.com

This compound's activity has also been explored in melanoma and sarcoma. Preclinical studies in murine models of melanoma and sarcoma have indicated that this compound can exert antitumor effects bmj.com. This is thought to involve increasing the number of tumor-infiltrating CD8+ cells and decreasing regulatory T cells (Tregs) bmj.com.

In melanoma, preclinical studies have demonstrated variable inhibition of melanoma cell growth by this compound in vitro spandidos-publications.comnih.gov. Sensitivity to this compound has been linked to the presence of c-Kit alterations (mutation or amplification) in melanoma cell lines aacrjournals.org. Highly sensitive melanoma cell lines with c-Kit alterations showed IC50 values in the picomolar to nanomolar range, while resistant lines had significantly higher IC50 values aacrjournals.org. This compound has also been shown to inhibit proliferation in primary melanoma cells by disrupting Src-ERK signaling spandidos-publications.comnih.gov.

A Phase 2 trial (E2607) assessed the efficacy of this compound in patients with unresectable locally advanced or stage IV mucosal, acral, and vulvovaginal melanomas, subtypes where c-KIT mutations play a critical role ascopubs.org. Preliminary results from this trial indicated that this compound is an active agent in these melanoma subtypes ascopubs.org. Among 17 evaluable patients in stage II of the study, 4 achieved a partial response (23.5%) and 6 had stable disease (35%) ascopubs.org.

Studies in sarcoma, such as osteosarcoma, are also ongoing plos.org.

Gastric Cancer

This compound is being investigated for its potential in treating gastric cancer. Studies have explored its effects on gastric cancer cell lines, noting its ability to inhibit cell growth and migration. Research indicates that this compound targets several kinases relevant in gastric cancer, including SRC and DDR2. Its efficacy has been observed in gastric cancers lacking E-cadherin expression, suggesting a potential therapeutic strategy for this specific molecular subtype. Targeting the DDR2-SRC-AKT3 axis with this compound is considered a promising approach for gastric cancers deficient in E-cadherin. nih.gov The effectiveness of this compound can vary among different gastric cancer cell lines, and this differential effect does not appear to correlate with the basal SRC activity of the cell line. researchgate.net this compound has been identified as an efficient inhibitor of migration and invasion in gastric cancer cells. uni.lu Kinome-wide analysis has identified several kinase targets of this compound relevant to gastric cancer cell invasion, including members of the SRC family (SRC, FRK, LYN, YES) and other kinases such as DDR1, ABL2, SIK2, RIPK2, EPHA2, and EPHB2. uni.lu The expression levels of kinases like FRK, DDR1, and SRC have been found to be significantly higher in metastatic gastric cancer samples. uni.lu

Non-Oncological Basic Research

Beyond its applications in cancer, this compound is being explored in basic research for its effects on various non-oncological processes and conditions.

This compound has emerged as a prominent senolytic agent, capable of selectively inducing apoptosis in senescent cells. wikipedia.orgguidetopharmacology.orgmdpi.com Senescent cells, characterized by irreversible cell cycle arrest and the secretion of pro-inflammatory factors (senescence-associated secretory phenotype - SASP), accumulate with age and contribute to tissue dysfunction and age-related diseases. guidetopharmacology.org this compound, often used in combination with quercetin, has been shown to effectively eliminate senescent cells in various tissues in mouse models, leading to improvements in physical function and reduced senescent cell burden. guidetopharmacology.orgwikipedia.orgciteab.comuni.luguidetopharmacology.org This combination has been investigated in human studies for conditions associated with cellular senescence, such as idiopathic pulmonary fibrosis and diabetic kidney disease, demonstrating a reduction in senescent cell markers in adipose tissue. guidetopharmacology.orgwikipedia.orgciteab.commims.com The combination of this compound and quercetin works by targeting pro-survival networks that protect senescent cells from apoptosis. guidetopharmacology.org

Research findings on the senolytic effects of this compound (often with Quercetin) in various models:

This compound's mechanism as a senolytic agent involves inducing apoptosis by inhibiting Src kinase, while quercetin is reported to inhibit the anti-apoptotic protein Bcl-xL. wikipedia.org

Investigations into this compound's effects extend to muscle diseases, including Duchenne Muscular Dystrophy (DMD). Studies in animal models, such as zebrafish and mice, have shown promising results. In zebrafish models of DMD, this compound treatment led to a notable improvement in the condition of the fish, including increased swimming ability (further and longer) and improved physical appearance of the musculature. nih.govwikidata.orgsenescence.infociteab.com This suggests that this compound could potentially slow muscle deterioration in DMD by targeting proteins like dystroglycan, which plays a role in maintaining healthy muscle tissue. nih.govwikidata.orgsenescence.info this compound was found to decrease the levels of phosphorylated β-dystroglycan and increase the relative levels of non-phosphorylated β-dystroglycan in dystrophic zebrafish. wikidata.org

However, research also indicates that this compound can influence muscle differentiation and regeneration. In studies using mouse models, this compound suppressed the proliferation of myoblasts and promoted their fusion in vitro. wikipedia.orgguidetopharmacology.orgfishersci.ca During muscle regeneration in mice, this compound increased the gene expression of myogenic-related genes but resulted in abnormally thin muscle fibers and disrupted normal muscle regeneration. wikipedia.orgguidetopharmacology.orgfishersci.ca These findings suggest that while this compound may hold promise for certain aspects of muscle diseases like DMD, its effects on muscle regeneration require careful consideration. wikipedia.orgguidetopharmacology.orgfishersci.ca Studies in mice indicated that this compound did not cause severe muscle tissue damage under normal conditions. wikipedia.orgresearchgate.net

This compound has shown potential in the treatment of radiation-induced skin ulcers, a prevalent complication of radiotherapy. mybiosource.com Research, including studies using network pharmacology and molecular docking, has explored the potential targets and signaling pathways involved in this compound's activity against radiation ulcers. acs.orgciteab.com These studies suggest that this compound may exert its effects by regulating targets such as EGFR, ERBB2, FYN, JAK2, KIT, and SRC. acs.orgciteab.com Pathways potentially involved include the EGFR tyrosine kinase inhibitor resistance, PI3K-Akt, and ErbB signaling pathways. acs.orgciteab.com Animal studies have indicated that this compound, in combination with quercetin, can promote the healing of radiation ulcers, potentially through the removal of senescent cells. mybiosource.comciteab.com

Effects on Muscle Diseases (e.g., Duchenne Muscular Dystrophy)

Immunomodulatory Effects and Applications

This compound is known to possess immunomodulatory properties, influencing various components of the immune system. mdpi.comfishersci.cabohrium.comguidetopharmacology.org These effects are an area of active research, particularly in the context of enhancing anti-tumor and anti-viral immunity.

This compound's immunomodulatory effects are particularly relevant in the context of hematological malignancies like chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). This compound treatment has been associated with changes in immune cell profiles, including an increase in populations of natural killer (NK) cells, large granular lymphocytes (LGLs), and CD8+ T cells, along with a reduction in regulatory T cells (Tregs). mdpi.comfishersci.caguidetopharmacology.orgharvard.edunih.gov This expansion of cytotoxic cells, such as NK and T-LGL cells, has been correlated with improved anti-leukemic responses in patients. mdpi.comfishersci.ca

Studies have shown that this compound can increase the absolute number of lymphocytes, including CD8+ T cells, in circulation. guidetopharmacology.org The increase in NK cells, particularly memory-like NK subsets, has been observed and is associated with activity against both leukemic cells and cytomegalovirus (CMV) infected cells. mdpi.comnih.gov Some research suggests that the development of LGL expansion with this compound may be associated with prior immunity to CMV. mdpi.comfishersci.canih.gov

This compound's influence on T cells includes promoting Th1-type responses in granzyme B expressing T-cells, which are capable of producing IFN-γ, important for tumor control. guidetopharmacology.org While in vitro studies sometimes show inhibition of T-cell function with constant this compound presence, in vivo studies suggest that the pharmacokinetics of this compound, with a short half-life and peak plasma concentrations occurring shortly after intake, may lead to enhanced anti-leukemia immune activity. guidetopharmacology.org

The combination of this compound with immunotherapy agents, such as blinatumomab, is also being investigated in Ph+ ALL, showing a marked host immunomodulatory effect with increased NK, T-NK, and CD8+ T cells and a reduction of Tregs. harvard.edu This sustained immune modulation observed with this compound and blinatumomab may contribute to disease control. harvard.edu

Increase in Cytotoxic Lymphocyte Counts (NK cells, CTLs)

This compound treatment has been associated with an increase in cytotoxic lymphocyte counts in the peripheral blood, including Natural Killer (NK) cells and Cytotoxic T Lymphocytes (CTLs). This phenomenon has been observed rapidly after this compound administration, although the precise underlying mechanism is still being elucidated. nih.govnih.gov Studies investigating the influence of this compound on signal transduction pathways in cytotoxic lymphocytes from CML patients treated with this compound, imatinib, or nilotinib revealed that only this compound-treated patients showed inhibition of multiple signaling pathways. nih.govnih.gov The magnitude of pERK and pAKT inhibition was closely linked to the increase in NK cells and CTLs, respectively, and these responses were more pronounced in patients positive for cytomegalovirus (CMV) IgG. nih.govnih.gov This suggests a direct effect of this compound on these signaling pathways within cytotoxic lymphocytes contributes to their mobilization. nih.govnih.gov

Expansion of Memory-like NK Cells and γδ T Cells

Several studies have reported that this compound promotes the expansion of memory-like NK cells and γδ T cells. mdpi.comnih.govresearchgate.net This expansion has been correlated with improved control of CML after treatment withdrawal in some patients. mdpi.comresearchgate.net The expanded lymphocyte populations in patients receiving this compound have been shown to contain both CD3+CD8+ effector memory T-cells and CD3−CD16+CD56+ NK cells. researchgate.netmdpi.com This large granular lymphocyte (LGL) expansion is associated with an improved anti-leukemic response in both CML and Ph+ ALL patients. researchgate.net The expansion of memory-like NK cells, particularly the NKG2C+CD57+ subset, is hypothesized to contribute to long-term memory and high cytotoxic activity against CML, potentially persisting even after this compound treatment interruption. encyclopedia.pub This expansion appears to be driven by previous infection with CMV, even in the absence of viremia. researchgate.net

Potential Role in HIV Infection

This compound's immunomodulatory properties and off-target effects suggest a potential role in the context of HIV infection. mdpi.comfrontiersin.org this compound has shown the ability to inhibit HIV-1 replication in vitro. frontiersin.orgresearchgate.nettandfonline.com This may be mediated by the inhibition of SAMHD1 phosphorylation in CD4+ T cells, a restriction factor that decreases intracellular dNTP levels required for viral replication. mdpi.comfrontiersin.orgresearchgate.nettandfonline.com By preserving SAMHD1 antiviral activity and inhibiting CD4+ T cell activation and proliferation, this compound could potentially reduce the establishment and maintenance of viral reservoirs. mdpi.comresearchgate.net

Studies have indicated that CD4+ T cells from CML patients treated with this compound were resistant to ex vivo HIV-1 infection. mdpi.comfrontiersin.org The potentiation of subpopulations like memory-like NK cells and γδ CD8+ T cells, which are associated with low viral reservoirs and persistent HIV control, could be key against HIV-1 infection. mdpi.comnih.gov Research suggests that this compound could activate NK cells by upregulating activating receptors and reducing inhibitory interactions, leading to the killing of HIV-infected cells. mdpi.com

A study involving individuals with HIV and chronic myeloid leukemia receiving both antiretroviral therapy and this compound demonstrated a significantly smaller viral reservoir with reduced reactivation potential compared to individuals on antiretroviral therapy alone. irsicaixa.es This suggests that this compound, in combination with antiretroviral treatment, could contribute to the reduction of the viral reservoir in people with HIV. irsicaixa.es

Identification of Predictive Molecular Markers

Identifying molecular markers that can predict response to this compound is crucial for patient selection and monitoring efficacy. Preclinical studies, particularly in solid tumors like prostate cancer, have utilized gene expression profiling to identify potential predictive markers. nih.govnih.govascopubs.org These studies have identified genes whose expression levels correlate with in vitro sensitivity to this compound. nih.govnih.govascopubs.org For instance, in prostate cancer, "basal type" cell lines with high expression of cytokeratin 5 and low expression of androgen receptor or prostate specific antigen were found to be sensitive to this compound. nih.govnih.govascopubs.org Urokinase-type plasminogen activator (uPA) and EphA2, a target of this compound, have also been identified as potential predictive and surrogate biomarkers in preclinical models. nih.govnih.govascopubs.orgaacrjournals.org

Optimization of Dosing Regimens and Schedules

Optimization of this compound dosing regimens and schedules aims to maintain efficacy while minimizing adverse events and improving patient quality of life. nih.govresearchgate.net The currently approved doses resulted from trials focused on maximizing efficacy and minimizing adverse events. nih.govresearchgate.net Studies have shown that this compound at a dose of 100 mg once daily demonstrated durable efficacy and a tolerable long-term safety profile in CML-CP patients. nih.govresearchgate.net This once-daily regimen at 100 mg is now a recommended dose for newly diagnosed CML-CP. nih.govresearchgate.net

Research also explores intermittent dosing schedules, such as "on-off" regimens, which have shown potential in reducing toxicity while maintaining efficacy in some patients resistant or intolerant to imatinib. researchgate.net These strategies aim to balance drug exposure with the potential for adverse effects. nih.govresearchgate.netmdpi.com

Exploring Low-Dose this compound Therapy

The exploration of low-dose this compound therapy is another strategy being investigated to potentially maintain efficacy while reducing toxicity. Studies and case reports suggest that initiating TKIs at lower doses or implementing dose reductions may maintain efficacy while minimizing treatment-related adverse events. nih.govfrontiersin.org

Targeting Transcriptional Plasticity

Transcriptional plasticity, the ability of cancer cells to alter their gene expression profiles in response to environmental cues or therapeutic pressure, is a significant contributor to drug resistance and tumor progression. Research indicates that this compound may influence this process, offering potential strategies to overcome resistance and enhance therapeutic outcomes.

Studies in pre-BCR+ acute lymphoblastic leukemia (ALL) have investigated mechanisms of resistance to this compound, highlighting the role of transcriptional plasticity. Acquired resistance in these cells was partly attributed to the upregulation of alternative pathways, such as the WNT pathway, through a mechanism suggesting transcriptional plasticity nih.govnih.gov. Depletion of the transcriptional co-activator CBP was shown to increase sensitivity to this compound by downregulating the transcription of the pre-BCR signaling pathway, which is associated with this compound sensitivity nih.govnih.gov. Furthermore, small molecules capable of disrupting the interaction between CBP and the CREB KID domain or β-catenin demonstrated promising preclinical efficacy in combination with this compound, suggesting approaches to ameliorate this compound sensitivity and prevent resistance in ALL nih.gov.

In melanoma cells with c-Kit alterations, this compound was found to stimulate its own mechanism of resistance by activating the CRTC3/MITF/Bcl-2 pathway at clinically relevant doses ulb.ac.be. This activation involves increased MITF and its downstream target Bcl-2 through the CRTC3 pathway, which in turn activates CREB-regulated transcription of MITF ulb.ac.be. Overexpression of MITF rendered melanoma cells resistant to all this compound concentrations tested ulb.ac.be. Selective inhibition of Bcl-2 or its knockout restored sensitivity to this compound, validating the involvement of the MITF and Bcl-2 axis in this compound resistance in melanoma ulb.ac.be.

Investigations in pancreatic cancer using bioinformatics analysis to understand this compound resistance mechanisms identified differentially expressed genes involved in various pathways, including "transcriptional misregulation in cancer" spandidos-publications.com. This suggests that altered transcriptional programs contribute to this compound resistance in this cancer type spandidos-publications.com.

Research in malignant pleural mesothelioma cell lines has explored this compound's ability to modulate sensitivity to other chemotherapeutic agents, such as pemetrexed oncotarget.com. These studies suggest that this compound can influence transcriptional regulation, potentially through its inhibition of SRC family kinases, which can impact the expression of genes like thymidylate synthase (TS) oncotarget.com. This compound treatment was shown to suppress TS protein expression and downregulate TS promoter activity, suggesting a role in sensitizing cells to pemetrexed by influencing transcriptional control oncotarget.com.

Moreover, this compound has been identified as a drug that could potentially overcome resistance to other targeted therapies, such as Gefitinib in lung cancer cells, by influencing altered pathways that contribute to resistance frontiersin.org. This highlights the potential of this compound to impact transcriptional rewiring that occurs in resistant cells frontiersin.org.

Modulating Drug Transport

Drug transporters, particularly those belonging to the ATP-binding cassette (ABC) transporter family, play a crucial role in the absorption, distribution, metabolism, and excretion of many drugs, including tyrosine kinase inhibitors like this compound mdpi.comfrontiersin.org. These transporters can significantly impact the intracellular concentration of this compound, influencing its efficacy and contributing to drug resistance frontiersin.orgpensoft.net.

Studies have confirmed that the cellular efflux of this compound is partially regulated by drug transporters, both in vivo and in vitro frontiersin.org. Several efflux proteins from the ABC transporter family, including ABCB1 (MDR1/P-gp), ABCG2 (BCRP), and ABCC6 (MRP6), have been reported to affect this compound diffusion frontiersin.org. Cell models have shown that this compound is a substrate for both P-gp and BCRP frontiersin.orgnih.gov. Overexpression of ABCB1 or ABCG2 protein has been shown to reduce intracellular this compound accumulation, leading to an increase in the half-maximal inhibitory concentration (IC50) of this compound frontiersin.orgpensoft.net. This effect could be modulated by inhibitors of these transporters frontiersin.org. Similarly, inhibition of ABCC6 in BCR-ABL1+ cell lines reduced this compound efflux, resulting in a significant decrease in this compound's IC50 frontiersin.org.

The importance of P-gp and BCRP in limiting this compound distribution has been particularly noted in the central nervous system (CNS) mdpi.comfrontiersin.orgnih.gov. In vitro studies indicate that cellular delivery of this compound is significantly limited by active efflux mediated by both P-gp and BCRP nih.gov. Permeability studies showed greater transport in the basolateral-to-apical direction than in the apical-to-basolateral direction due to active efflux by these transporters nih.gov. In vivo studies in mice have demonstrated that this compound brain distribution is significantly increased in the absence of functional P-gp and BCRP, or when these transporters are inhibited mdpi.comnih.gov. Simultaneous inhibition of P-gp and BCRP resulted in a substantial increase in brain concentration nih.gov. These findings suggest that these transporters play a significant role in limiting the CNS delivery of this compound, which has implications for treating primary and metastatic brain tumors nih.gov.

While this compound is a substrate for ABCB1 and ABCG2, it can also act as an inhibitor of these proteins at higher concentrations, potentially influencing the transport of other substances semanticscholar.org. However, the clinical relevance of this compound-mediated P-gp inhibition at therapeutic plasma concentrations is considered limited mdpi.com.

Beyond ABCB1 and ABCG2, research has also explored the role of other transporters in this compound pharmacokinetics. A study investigating the contribution of ABCC4 (MRP4) to the absorption of oral this compound suggested that ABCC4 in the stomach facilitates its oral absorption nih.gov. Deficiency of Abcc4 in mice was associated with decreased systemic exposure to oral this compound, and this compound efflux from isolated mouse stomachs was impaired in the absence of Abcc4 nih.gov. This indicates a potential role for ABCC4 in gastric transport of this compound nih.gov.

Unlike some other tyrosine kinase inhibitors, this compound cellular uptake does not appear to be dependent on the activity of the human organic cation transporter 1 (hOCT1) semanticscholar.org.