Imatinib

BCR-ABL Oncoprotein Kinase Inhibition

The BCR-ABL fusion protein is a constitutively active tyrosine kinase resulting from the Philadelphia chromosome abnormality (t(9;22) translocation) in chronic myeloid leukemia (CML). drugbank.compharmgkb.org This aberrant oncoprotein drives uncontrolled cell proliferation and survival in CML. drugbank.comnih.govdroracle.aipharmgkb.org this compound specifically targets and inhibits the BCR-ABL tyrosine kinase by binding to its ATP-binding pocket in the inactive conformation. drugbank.comnih.govresearchgate.nettandfonline.comresearchgate.net This binding prevents the transfer of a phosphate group from ATP to tyrosine residues on substrate proteins, thereby blocking their activation and the subsequent transmission of proliferative signals to the nucleus. nih.govresearchgate.netresearchgate.net Consequently, this compound effectively suppresses the growth of BCR-ABL-positive cells and induces apoptosis, while largely sparing normal cells. nih.govpharmgkb.org

Platelet-Derived Growth Factor Receptor (PDGFR) Kinase Inhibition

This compound also acts as a potent inhibitor of the platelet-derived growth factor receptor (PDGFR) kinase, including both alpha and beta isoforms. drugbank.comdroracle.aicellagentech.com PDGFRs are receptor tyrosine kinases that regulate various cellular processes such as proliferation, differentiation, migration, and survival upon binding to their ligand, platelet-derived growth factor (PDGF). scbt.com In certain cancers, such as gastrointestinal stromal tumors (GISTs) and some myeloproliferative disorders, mutations in PDGFR can lead to its constitutive activation, driving aberrant cell growth. droracle.airesearchgate.netaacrjournals.orgonclive.com this compound inhibits PDGFR activity by binding selectively to its ATP-binding site, stabilizing the inactive conformation of the receptor. scbt.comresearchgate.net This interaction prevents autophosphorylation and the phosphorylation of downstream substrate molecules, thereby inhibiting downstream signaling cascades and subsequent cellular proliferation and survival. scbt.comresearchgate.netaacrjournals.org

c-KIT Kinase Inhibition

The c-KIT receptor tyrosine kinase, also known as the stem cell factor receptor (SCF-R), plays a crucial role in normal cell growth and development. drugbank.comdroracle.ai However, activating mutations in c-KIT are frequently observed in gastrointestinal stromal tumors (GISTs), leading to constitutive kinase activity and uncontrolled cell growth. drugbank.compharmgkb.orgaacrjournals.orgresearchgate.net this compound effectively inhibits both wild-type and certain mutant forms of c-KIT by occupying the ATP-binding pocket of the kinase domain in its inactive conformation. drugbank.comaacrjournals.orgcellagentech.comresearchgate.netpnas.org This binding prevents the phosphorylation of c-KIT substrates and subsequent activation of downstream signaling pathways, including the MAPK and Akt pathways, which are critical for cell proliferation and survival. cellagentech.comresearchgate.netstanford.edu It's important to note that certain c-KIT mutations, such as D816V in systemic mastocytosis, can render the kinase constitutively active in a conformation that this compound does not effectively inhibit, leading to resistance. pnas.orgwikipedia.orgashpublications.org

Molecular Interactions at the ATP-Binding Pocket

This compound's inhibitory mechanism involves its specific binding to the ATP-binding pocket within the kinase domain of its target enzymes (BCR-ABL, PDGFR, c-KIT). drugbank.comnih.govdroracle.airesearchgate.netresearchgate.netwikipedia.org This pocket is typically occupied by adenosine triphosphate (ATP) during the normal phosphorylation cycle. This compound acts as a competitive inhibitor, binding to this site and preventing ATP from accessing it. researchgate.netresearchgate.net this compound generally binds to the inactive conformation of the kinase. nih.govtandfonline.comscbt.comnih.gov For example, in BCR-ABL, this compound binding locks the kinase domain in an inactive, DFG-out/AL-closed conformation, preventing substrate binding and phosphorylation. nih.gov Molecular dynamics simulations indicate that this compound interacts with various regions of the Abl kinase, including the ATP-binding site, the interface with the SH2 domain, the myristoyl-binding site, the αG helix region of the C-lobe, and the PIF-binding site of the N-lobe. nih.gov At physiological pH, the 1-methylpiperazin-1-ium group nitrogen of this compound may be protonated, and simulations suggest that this compound binds to Abl in its protonated, positively-charged form. researchgate.net

Prevention of Substrate Phosphorylation

The core consequence of this compound binding to the ATP-binding pocket of its target kinases is the prevention of substrate phosphorylation. nih.govresearchgate.netresearchgate.netwikipedia.org By occupying the ATP-binding site, this compound blocks the transfer of a phosphate group from ATP to the tyrosine residues of target proteins. nih.govdroracle.airesearchgate.netresearchgate.netresearchgate.net This inhibition means that the normal substrates of these kinases cannot be phosphorylated and thus cannot become activated. As a result, the downstream signaling cascades that depend on these phosphorylation events are interrupted, leading to the inhibition of cell proliferation and the induction of apoptosis in affected cancer cells. nih.govdroracle.aiaacrjournals.orgresearchgate.netresearchgate.net

Ras/MapK Pathway Perturbations

The BCR-ABL oncogenic pathway exerts control over numerous downstream signaling cascades vital for neoplastic growth, including the Ras/MapK (Mitogen-activated protein kinase) pathway, which is intimately involved in cellular proliferation drugbank.com. This compound's primary inhibitory action on the BCR-ABL tyrosine kinase effectively disrupts this upstream activation, leading to downstream perturbations in the Ras/MapK pathway drugbank.comdroracle.ainih.gov. Research findings indicate that this compound can inhibit cell proliferation, partly through the inactivation of extracellular signal-regulated kinase (ERK), a key component of the MAPK pathway longdom.org. This suggests that this compound's therapeutic effects involve the dampening of hyperactive proliferative signals transmitted via the Ras/MapK cascade in malignant cells longdom.org.

Src/Pax/Fak/Rac Pathway Modulation

Another critical pathway regulated by the BCR-ABL pathway, and consequently modulated by this compound, is the Src/Pax/Fak/Rac pathway, which plays a significant role in cellular motility and adhesion drugbank.com.

Src Kinase : Src family kinases (SFKs) are non-receptor tyrosine kinases implicated in various signal transductions and are often aberrantly expressed or activated in numerous cancers researchgate.net. As BCR-ABL can activate SFKs, this compound's inhibition of BCR-ABL indirectly impacts Src activity drugbank.comnih.govresearchgate.net.

Focal Adhesion Kinase (FAK) : FAK is a tyrosine kinase crucial for tumor progression, affecting proliferation, survival, invasion, and metastasis aacrjournals.org. FAK activation typically involves autophosphorylation at tyrosine 397 (Y397), which then serves as a docking site for Src-family kinases and phosphatidylinositol 3-kinase (PI3K) aacrjournals.org. By modulating upstream kinases, this compound can influence FAK activity, thereby affecting cellular adhesion and motility drugbank.com. Experimental FAK inhibitors, such as GSK2256098 and PF-562271, have been developed to investigate the anti-tumor effects of FAK inhibition guidetopharmacology.orgnih.gov.

Rac : Rac1, a member of the Rho family of small GTPases, is involved in cytoskeletal reorganization, cell growth, and cell motility drugbank.comgenecards.org. Inhibition of the BCR-ABL pathway by this compound can disrupt the signaling that drives Rac activity, thereby impacting processes like cell migration and adhesion in malignant cells drugbank.com.

PI3K/AKT/BCL-2 Pathway Regulation

The PI3K/AKT/BCL-2 pathway is a major signaling cascade that regulates cell survival, proliferation, and growth, often contributing to oncogenic transformation when activated drugbank.commdpi.com. This compound's inhibitory effects on the BCR-ABL tyrosine kinase extend to the regulation of this pathway drugbank.com.

PI3K/AKT : this compound's inhibition of BCR-ABL can lead to the disruption of downstream PI3K activation, thereby blocking AKT signaling pathways longdom.orgjcpjournal.org. The activation of PI3K subsequently phosphorylates AKT, promoting cell survival mdpi.com. By inhibiting this axis, this compound contributes to the suppression of malignant cell growth jcpjournal.org.

BCL-2 : BCL-2 is a key anti-apoptotic protein nih.gov. The PI3K/AKT pathway's downstream effects include the regulation of BCL-2 family proteins. By downregulating survival signals transmitted through the PI3K/AKT pathway, this compound promotes an environment conducive to apoptosis by modulating the balance of pro- and anti-apoptotic BCL-2 family proteins drugbank.comnih.gov.

Cell Cycle Arrest Induction

This compound's molecular actions culminate in the induction of cell cycle arrest in various malignant cell types, thereby halting uncontrolled proliferation nih.gov. This effect is often observed in a dose-dependent manner longdom.orgplos.org. For instance, this compound treatment has been shown to induce G0/G1 phase arrest in human skin squamous cell carcinoma (SSCC) cells (A431), multiple myeloma cells, HepG2 hepatocellular carcinoma cells, and several osteosarcoma cell lines (MG-63, MOS-J, OSRGA) longdom.orgjcpjournal.orgplos.org. In other cell lines, such as HOS and POS-1 osteosarcoma cells, as well as MCF7 and T-47D breast cancer cells, this compound can lead to arrest in the S or G2/M phase plos.orgdovepress.com. Gastric cancer cells treated with this compound have also shown G2/M phase arrest spandidos-publications.com. Mechanistically, this cell cycle arrest is linked to the downregulation of S-phase kinase-associated protein 2 (SKP2) and the concomitant upregulation of P21CIP1 (p21) longdom.orgjcpjournal.org. SKP2 is an E3 ubiquitin ligase component that promotes the degradation of cell cycle inhibitors like P21CIP1, so its downregulation by this compound leads to P21CIP1 stabilization and cell cycle inhibition longdom.orgjcpjournal.org.

Table 1: Examples of this compound-Induced Cell Cycle Arrest in Various Cell Lines

Apoptosis Induction in Malignant Cells

Beyond cell cycle arrest, this compound is a potent inducer of apoptosis, or programmed cell death, in malignant cells drugbank.comnih.gov. This crucial mechanism contributes significantly to its therapeutic efficacy droracle.ainih.gov. This compound induces apoptosis in cells harboring the BCR-ABL fusion protein, such as those found in chronic myeloid leukemia (CML), and in gastrointestinal stromal tumor (GIST) cells that express an activating c-Kit mutation drugbank.comdroracle.ainih.gov. The induction of apoptosis is a direct consequence of this compound blocking the proliferative signals originating from these constitutively active tyrosine kinases nih.gov. Studies have demonstrated that this compound induces mitochondria-mediated apoptosis in gastric cancer cells, a process that involves endoplasmic reticulum (ER) stress-associated activation of c-Jun NH2-terminal kinase (JNK) spandidos-publications.com. Furthermore, this compound has been shown to induce cell death in osteosarcoma cell lines, with the mechanism being partly dependent on caspase activation plos.org. In breast cancer cell lines, significant apoptosis induction was observed after 96 hours of this compound treatment, following an initial period of cell cycle arrest dovepress.com. This indicates a time-dependent progression from cytostasis to cell death in some contexts dovepress.com.

Selective Suppression of Oncogene-Expressing Cell Lines (e.g., BCR-ABL, K562)

Imatinib potently inhibits the growth of cells expressing the p210 BCR-ABL fusion protein, demonstrating selective antiproliferative activity ashpublications.org. This selective effect was confirmed across numerous cell lines derived from CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), while Ph-negative cell lines remained unaffected ashpublications.org.

For instance, this compound exhibited significant growth inhibition in the K562 cell line, a widely used CML cell model that constitutively expresses BCR-ABL ashpublications.orgashpublications.orgjcancer.org. The inhibitory concentration 50 (IC50) for this compound in inhibiting proliferation generally mirrored its IC50 values for inhibiting BCR-ABL kinase activity in cellular assays ashpublications.org. Exposure to this compound ultimately leads to apoptotic cell death in these sensitive cell lines ashpublications.org.

It was observed that this compound potently inhibited all ABL tyrosine kinases, including cellular ABL, viral ABL (v-ABL), and BCR-ABL ashpublications.org. Studies using purified enzymes or immunoprecipitations showed that this compound inhibited ABL kinase activity with IC50 values ranging between 0.1 and 0.35 µM ashpublications.org.

Colony-Forming Unit Assays

Colony-forming unit (CFU) assays are crucial for assessing the impact of compounds on hematopoietic progenitor cells. This compound has been shown to inhibit the growth of colony-forming units, specifically granulocyte/macrophage colony-forming units (CFU-GM) and erythroid burst-forming units (BFU-E), in a dose-dependent manner ashpublications.org. This inhibition was observed even at low concentrations of this compound, such as 1.25 µM, which reduced the growth of CFU-GM in clonogenic assays ashpublications.orgnih.gov.

A reduction in colony-forming capacity due to this compound treatment was detectable from concentrations as low as 1.25 µM for total colonies, significantly affecting BFU-Es from 2.5 µM and CFU-GMs from 0.625 µM ashpublications.org. This compound treatment also led to a reduction in colony size compared to controls ashpublications.org. This effect on normal progenitor cells indicates that this compound can influence hematopoietic cell proliferation, although its primary clinical efficacy is directed at malignant BCR-ABL-positive cells bjournal.org.

Design Principles for Novel this compound Analogues

The development of this compound was a prime example of rational drug design, initiated after the identification of the Philadelphia chromosome mutation and the hyperactive BCR-ABL protein wikipedia.orguniversiteitleiden.nl. The initial lead compound, a 2-phenylaminopyrimidine derivative, was identified through high-throughput screening wikipedia.orgpagepress.org. This compound, however, had low potency and poor specificity, inhibiting both serine/threonine and tyrosine kinases ashpublications.orgpagepress.org.

Subsequent structural optimization involved systematic modifications to enhance its selectivity and potency:

Enhancement of Cellular Activity: The addition of a 3′-pyridyl group at the 3′-position of the pyrimidine ring significantly enhanced the cellular activity of the derivatives ashpublications.orgpagepress.org.

Improved Tyrosine Kinase Activity: Introducing a benzamide group to the phenyl ring further enhanced activity against tyrosine kinases ashpublications.orgpagepress.org.

Reduced PKC Inhibition: A key observation from structure-activity relationship (SAR) analysis was that substitutions at the 6-position of the anilino phenyl ring led to a loss of protein kinase C (PKC) inhibition ashpublications.orgpagepress.org. The introduction of a "flag-methyl" group at this position either retained or enhanced activity against ABL tyrosine kinases ashpublications.orgpagepress.org.

Increased Solubility and Bioavailability: The attachment of an N-methylpiperazine group markedly improved water solubility and oral bioavailability, making it a clinically viable drug ashpublications.orgpagepress.org.

These design principles, leveraging medicinal chemistry and understanding of protein kinase binding sites, have guided the development of subsequent generations of ABL kinase inhibitors and novel this compound analogues nih.govnih.govaacrjournals.org. The goal is often to expand the structural diversity of BCR-ABL inhibitors and to overcome acquired resistance mechanisms, such as those arising from mutations in the BCR-ABL kinase domain benthamdirect.compnas.orgmdpi.com.

Structure-Activity Relationship (SAR) Studies of this compound Derivatives

SAR studies are crucial for understanding how modifications to a compound's chemical structure influence its biological activity, and these have been extensively performed for this compound and its derivatives benthamdirect.commdpi.comacs.org. These studies aim to identify key pharmacophoric features and optimize drug properties like potency, selectivity, and pharmacokinetic profiles.

For this compound, the 2-phenylaminopyrimidine scaffold is a fundamental pharmacophoric fragment mdpi.comresearchgate.net. SAR studies have explored modifications to various parts of the this compound molecule:

Benzene (A ring) and Piperidine (E ring) Substitutions: Introducing benzene and piperidine rings instead of the pyridine (A ring) and piperazine (E ring) in this compound has been shown to significantly enhance potency against K562 and HL-60 cell lines benthamdirect.com. This is consistent with docking results, suggesting improved interactions with the target benthamdirect.com.

Phenylamino Moiety Modifications: Substitutions in the -3 and -4 positions of the phenylamino moiety have led to improved potency and selectivity in both target-based and cell-based assays for certain pyrido[2,3-d]pyrimidin-7-one compounds, a class of Abl kinase inhibitors nih.gov.

Specific Group Importance: The importance of specific groups, such as the CF₂ group, has been highlighted in studies of new this compound derivatives, where its absence led to a loss of activity mdpi.com.

Overcoming Resistance: SAR studies have been instrumental in designing novel derivatives capable of overcoming this compound resistance, particularly mutations like T315I pnas.orgmdpi.com. For example, thiazolo[5,4-b]pyridine derivatives were synthesized, and SAR studies identified compounds with higher enzymatic and cellular activities against c-KIT mutants, including those resistant to this compound mdpi.com. One such derivative, 6r, demonstrated 8.0-fold higher enzymatic inhibitory activity against a c-KIT V560G/D816V double mutant and 23.6-fold higher antiproliferative activity on HMC1.2 cells than this compound mdpi.com.

The ongoing SAR research continues to provide useful information for the rational design of new compounds with improved properties, aiming to enhance efficacy and overcome resistance mechanisms in CML and other cancers where ABL or related kinases are implicated benthamdirect.commdpi.comijpsr.com.

Cytostatic Effects of this compound Analogues on Cancer Cell Lines

The development of chemical analogues of existing therapeutics, such as this compound, represents a crucial strategy in drug discovery. This approach aims to enhance potency, improve selectivity, overcome drug resistance, or reduce off-target effects. Preclinical research into this compound analogues has demonstrated diverse cytostatic effects across various cancer cell lines, offering insights into structure-activity relationships and potential future therapeutic candidates.

Research Findings

Several studies have explored the antiproliferative capabilities of novel this compound derivatives. One investigation synthesized new analogues incorporating isatins and the phenylamino-pyrimidine pyridine (PAPP) scaffold, which is a key pharmacophore of this compound nih.gov. These compounds were evaluated for their antiproliferative activity against human lung adenocarcinoma (A549) and chronic myeloid leukemia (K562) cell lines. Notably, certain 3,3-difluorinated this compound derivatives demonstrated significantly superior potency against A549 cells compared to this compound itself. Specifically, compounds 3a, 3c (5-chloro-3,3-difluorinated), and 3d (5-bromo-3,3-difluorinated) exhibited IC50 values of 7.2 µM, 6.4 µM, and 7.3 µM, respectively, while this compound's IC50 against A549 was 65.4 µM nih.gov. In contrast, for the K562 cell line, while this compound showed an exceptionally low IC50 of 0.08 µM, the derivative 3b (3,3-difluoro-5-methylated) had an IC50 of 35.8 µM at 10 µM, indicating that the potency against this cell line was not universally improved for all analogues nih.gov.

Another series of this compound derivatives, N-(2,5-dimethylphenyl)-4-pyridin-3-ylpyrimidin-2-amine compounds bearing a 2-chloroquinoline motif, were synthesized and screened for antiproliferative activity against human alveolar adenocarcinoma (A549) and human breast adenocarcinoma (MCF7) cell lines ijper.org. At a concentration of 10 µM, these compounds showed moderate cell growth inhibition. Among them, compound 4c, which features a dimethoxy group at the 6 and 8 positions of the 2-chloroquinoline ring, exhibited the highest antiproliferative activity, resulting in 35.21% cell viability for A549 and 30.36% for MCF7 cell lines ijper.org. This suggests that specific structural modifications can retain, and in some contexts, optimize the anticancer activity of this compound derivatives ijper.org.

Further research into this compound derivatives evaluated two compounds, 2a and 2b, against breast cancer (MCF-7) and colorectal cancer (HCT116) cell lines impactfactor.orgresearchgate.net. Compound 2b demonstrated superior activity against the HCT116 cell line with an IC50 of 15.88 µg/mL, compared to this compound's 18.52 µg/mL. However, against the MCF-7 cell line, both compounds 2a and 2b showed lower potency (IC50s of 127.35 µg/mL and 125.88 µg/mL, respectively) compared to this compound's 19.34 µg/mL impactfactor.orgresearchgate.net. Interestingly, compound 2b also exhibited improved cytotoxic activity on normal non-cancerous MDCK kidney cells, meaning it was less toxic to these cells compared to this compound, suggesting a potentially better therapeutic index impactfactor.orgresearchgate.net.

In the context of Bcr-Abl inhibition, new this compound analogues have been developed and assessed for their cytostatic effects on various human cancer cell lines, including K562 (chronic myeloid leukemia) and HL-60 (acute myeloid leukemia) benthamdirect.comresearchgate.net. One such analogue, compound 1h, displayed lower IC50 values for both K562 and HL-60 cells compared to this compound, indicating enhanced potency. Studies further revealed that compound 1h was superior to this compound in inhibiting Bcr-Abl expression and inducing pro-apoptotic effects in K562 cells benthamdirect.comresearchgate.net. Structural analysis indicated that replacing the pyridine (A ring) and piperazine (E ring) moieties in this compound with benzene and piperidine rings, respectively, significantly enhanced the potency of the analogue against K562 and HL-60 cell lines benthamdirect.comresearchgate.net.

Data Tables

The following tables summarize the cytostatic effects of various this compound analogues on different cancer cell lines, based on published research findings.

Table 1: Cytostatic Activity of this compound Derivatives (Isatin/PAPP Scaffold) on Cancer Cell Lines

Table 2: Cytostatic Activity of this compound Derivatives (Quinoline Scaffold) on Cancer Cell Lines

Table 3: Cytostatic Activity of Other this compound Derivatives on Cancer Cell Lines

ABL Kinase Domain Point Mutations

Point mutations within the ABL kinase domain of the BCR-ABL fusion protein are the most frequently identified mechanism of acquired resistance to this compound, observed in 30-50% of cases thieme-connect.comashpublications.orgnih.gov. Over 100 distinct amino acid substitutions have been identified, with around 40 different amino acid substitutions reported to date aacrjournals.orgbiorxiv.orgpnas.orgnih.gov. These mutations prevent this compound from binding effectively to its target without necessarily affecting ATP binding or kinase activity aacrjournals.orgehaweb.org. The frequency of these mutations varies with disease phase, ranging from 25-30% in early chronic phase (CP) CML patients on first-line this compound to approximately 70-80% in blast crisis (BC) patients ashpublications.org.

A table summarizing the common ABL kinase domain mutations and their impact on this compound resistance is provided below.

Mutations Affecting this compound Binding Site

This compound functions by competitively targeting the ATP binding site within the ABL kinase domain, thereby stabilizing the kinase in a catalytically inactive conformation nih.govjnccn.orgpnas.org. Mutations affecting the this compound binding site can directly impair drug binding through steric hindrance or by destabilizing the inactive kinase conformation necessary for this compound binding aacrjournals.orgpnas.orgehaweb.orgpnas.org. The side chain of threonine 315 (T315) forms a hydrogen bond with this compound, making the T315I mutation particularly significant as it introduces an isoleucine, a bulkier amino acid, which sterically hinders this compound binding, leading to complete resistance aacrjournals.orgehaweb.orgjnccn.org. Other mutations, such as Y253F/H and E255K/V, also located in the ATP-binding site, can disrupt optimal drug interaction aacrjournals.orgashpublications.org.

P-loop (ATP Binding Site) Mutations

The P-loop (amino acids 248-256) is a highly conserved region of the ABL kinase domain responsible for ATP phosphate binding aacrjournals.orgjnccn.org. Mutations within the P-loop are the most frequently occurring this compound-resistant mutations, accounting for 36% to 48% of all mutations nih.gov. These mutations, such as G250E, Y253F/H, E255K/V, and M244V, often disrupt the proper positioning of the P-loop, preventing the kinase from adopting the inactive conformation required for this compound binding aacrjournals.orgnih.govjnccn.org. P-loop mutations are frequently observed in advanced-stage CML and Ph+ ALL patients and are often associated with progression from chronic phase to accelerated phase or blast crisis aacrjournals.org. Some P-loop mutations, like Y253F and E255K, have shown increased oncogenic potency relative to unmutated BCR-ABL and other mutated variants in in vitro studies nih.gov.

Catalytic (C) Domain and Activation Loop Mutations

Mutations can also occur in the catalytic (C) domain and the activation loop (A-loop) of the ABL kinase domain, impacting this compound binding and kinase activity nih.govsynnovis.co.uk. The A-loop is crucial for regulating kinase activity, and mutations like H396P can stabilize the active conformation of the kinase, which this compound is unable to bind jnccn.orgresearchgate.net. The M351T mutation, located at the base of the activation loop, is another common mutation that can confer resistance aacrjournals.orgjnccn.org. Mutations in these regions can alter the conformational dynamics of the protein, potentially leading to faster dissociation of this compound even if initial binding affinity is wild-type-like biorxiv.orgpnas.org.

Pre-existing Mutation Clones and Disease Phenotype

Research suggests that mutated BCR-ABL-expressing cells may pre-exist at low, undetectable levels in patients prior to this compound treatment nih.govunibo.itplos.org. These pre-existing clones can then expand under the selective pressure of this compound therapy, leading to acquired resistance and disease progression nih.govunibo.itresearchgate.net. The presence of such mutations, particularly those affecting drug binding directly or indirectly, has been associated with this compound resistance and disease progression researchgate.netamerihealth.com. Studies have used highly sensitive techniques like allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) to detect rare mutated cells in pre-treatment samples, supporting the theory of pre-existing mutations nih.govresearchgate.net. The detection of pre-existing BCR-ABL mutations in CD34+ stem/progenitor cells of newly diagnosed chronic-phase CML patients has been linked to subsequent this compound resistance researchgate.net. While the T315I mutation is not necessarily more likely to pre-exist than other resistance mutations, T315I cells tend to establish larger clones at diagnosis plos.org. The "fitness" of these mutant clones, their ability to proliferate and gain a selective advantage, is highly relevant to the risk of resistance and disease progression unibo.itplos.org.

BCR-ABL Gene Amplification and Protein Overexpression

Beyond point mutations, BCR-ABL gene amplification and subsequent protein overexpression represent another significant BCR-ABL dependent mechanism of this compound resistance researchgate.netaacrjournals.orgresearchgate.netresearchgate.netaacrjournals.orgconicet.gov.ar. This mechanism can lead to elevated ABL kinase activity, potentially overwhelming the inhibitory capacity of this compound researchgate.netresearchgate.net. BCR-ABL gene amplification is more commonly observed in advanced-phase disease aacrjournals.org. Studies have reported that overexpression of BCR-ABL transcript can be associated with this compound resistance, with increased expression levels hindering the therapeutic efficacy of this compound researchgate.net. This overexpression can herald disease progression, where genetic instability is higher, and oncogenic addiction might be reduced researchgate.net. The extent of BCR-ABL transcript overexpression linked to this compound resistance has been estimated to range from a few-fold to one log or more researchgate.net.

Systemic Exposure and Clearance Dynamics

MicroRNA Expression Profiles (e.g., miR-21, miR-26b, miR-451)

Hematopoietic Progenitor Cell Mobilization, Proliferation, and Differentiation

This compound has been observed to affect the mobilization, proliferation, and differentiation of hematopoietic progenitor cells nih.govscielo.brnih.govoup.combjournal.org. Studies indicate a dose-dependent decrease in the proliferation potential of CD34+ cells when exposed to this compound in vitro ashpublications.org. This inhibition is also reflected in a reduced colony-forming capacity, affecting both erythroid (BFU-E) and granulocyte/macrophage (CFU-GM) progenitor cells ashpublications.org. This effect on progenitor cells is a contributing factor to the myelosuppression observed in some treated patients nih.govscielo.broup.com. The inhibition of c-Kit signaling, a target of this compound, may partly explain the reduction in CFU-GM colony growth, as Stem Cell Factor (SCF) acting via c-Kit synergizes with other growth factors to stimulate progenitor cell formation scielo.brbjournal.org.

Table 1: Effects of this compound on Hematopoietic Progenitor Cells (in vitro) ashpublications.org

Impact on Hematopoietic Stem Cells

While this compound significantly affects hematopoietic progenitor cells, it generally leaves more primitive hematopoietic stem cells (HSCs) unaffected, or less affected, at standard therapeutic concentrations nih.govnih.govoup.comashpublications.org. However, some studies suggest that this compound might induce activation, expansion, and maturation of HSCs and multipotent hematopoietic progenitors (MPP1-4) in the bone marrow, especially at certain doses nih.govplos.org. Despite this, the most primitive, quiescent Philadelphia-positive (Ph+) leukemic stem cells (LSCs) often remain largely insensitive to this compound, contributing to disease persistence and potential relapse mdpi.comoncotarget.comashpublications.org.

Influence on Regulatory T Cells (Tregs)

This compound has a notable influence on regulatory T cells (Tregs), a critical population involved in maintaining peripheral tolerance. Clinical observations and preclinical studies indicate that this compound can inhibit the number and suppressive function of Tregs nih.govjst.go.jprupress.orgresearchgate.netspandidos-publications.com. This compound has been shown to impair Treg immunosuppressive function and FoxP3 expression, a key transcription factor for Treg lineage commitment, in vitro nih.gov. This effect is partly mediated by the drug's ability to reduce the activation of transcription factors STAT3 and STAT5 in Tregs, and to inhibit the phosphorylation of ZAP70 and LAT in the Treg T-cell receptor (TCR)-induced signaling cascade nih.gov. Furthermore, this compound's inhibition of lymphocyte-specific protein tyrosine kinase (LCK) appears to selectively induce apoptosis in effector Tregs (eTregs), which express lower levels of LCK and ZAP-70 compared to other T cells, making them more susceptible to signal-deprived apoptosis upon TCR signal inhibition rupress.orgbmj.com. This selective depletion of eTregs can enhance anti-tumor immune responses rupress.org.

Table 2: this compound's Effects on Regulatory T Cells (Tregs) nih.govrupress.org

Modulation of Antigen-Presenting Cells (APCs) Function and Differentiation

The effects of this compound on antigen-presenting cells (APCs) are complex and, at times, appear contradictory across different studies nih.gov. Some research suggests that this compound can negatively modulate dendritic cell (DC) development and down-regulate their antigen-presenting function nih.govashpublications.org. For example, in vitro exposure of human CD34+ progenitors to this compound has been shown to result in DCs with reduced expression of co-stimulatory molecules (CD80, CD40) and an inability to induce primary cytotoxic T lymphocyte (CTL) responses ashpublications.org. This compound may also inhibit the in vitro development of monocyte/macrophage lineages from normal human bone marrow progenitor cells ashpublications.org. Conversely, other studies report that this compound may enhance APC function and overcome tumor-induced CD4+ T-cell tolerance ashpublications.orgpnas.org. Treatment of APCs with this compound in vitro has been shown to enhance the activation of naive antigen-specific T cells and restore the responsiveness of tolerant T cells from tumor-bearing hosts ashpublications.org. This enhancement may be linked to the inhibition of c-kit phosphorylation in APCs ashpublications.org. This compound's influence on APCs can also involve modulating pathways like NF-κB signaling, which affects cytokine production, including IL-6 and TNF-α pnas.orgnih.gov.

Inhibition of Effector T Lymphocyte Functions

This compound has been documented to inhibit the proliferation and activation of both CD4+ and CD8+ effector T lymphocytes nih.govnih.govoup.comresearchgate.netresearchgate.netnih.govresearchgate.net. This inhibitory effect is dose-dependent and has been observed at therapeutically relevant concentrations researchgate.netresearchgate.netnih.gov. This compound can reduce antigen-specific interferon-gamma (IFN-γ) secretion from both CD4+ and CD8+ T-effector cells without necessarily causing T-cell viability loss researchgate.netnih.govresearchgate.net. The drug's influence on T-cell activation extends to reducing the expression of activation markers on CD3+ T cells researchgate.net. This modulation of T-cell function is attributed, in part, to this compound's interference with the T-cell receptor (TCR)-induced ZAP70 signaling pathway, potentially by targeting the tyrosine kinase Lck nih.govresearchgate.net. Notably, this inhibition of T-cell proliferation appears to be reversible upon removal of the drug researchgate.netnih.gov.

Table 3: Impact of this compound on Effector T Lymphocyte Functions researchgate.netnih.govresearchgate.netnih.gov

Cytotoxic T Cell Induction and Impairment

The induction of specific cytotoxic T cells (CTLs) appears to be impaired in chronic myeloid leukemia (CML) patients treated with this compound compared to those receiving interferon-alpha nih.govnih.govoup.comresearchgate.netcapes.gov.br. While primary CTL responses to viral infections like lymphocytic choriomeningitis virus (LCMV) may not be significantly impaired by this compound, the secondary expansion of antigen-experienced memory CTLs is reduced both in vitro and in vivo capes.gov.brnih.gov. This reduction in memory CTL expansion can lead to impaired protection against reinfection and a delayed onset of CTL-induced pathologies in disease models capes.gov.brnih.gov. This effect is particularly significant in the context of anti-leukemic immunity, where the long-term control of leukemia often relies on robust, persistent T-cell responses plos.org.

Natural Killer (NK) Cell Activity Modulation

This compound's influence on Natural Killer (NK) cells presents a nuanced picture. While some studies suggest that NK cells generally exhibit high resistance to the cytotoxic effects of this compound at clinically relevant concentrations, other research indicates modulatory effects on NK cell activity aai.org. For instance, this compound has been observed to increase the expression of NKG2D, an activating receptor on NK cells, and to decrease the production and release of MICA protein, a ligand for NKG2D frontiersin.org. This action contributes to the restoration of functional NKG2D signaling, which is crucial for NK cell cytotoxicity frontiersin.org.

However, conflicting findings exist, where this compound treatment, particularly in Bcr/Abl-expressing target cells, has been shown to decrease their susceptibility to NK-mediated lysis. This effect can involve the modulation of NKG2D ligands, alteration of GM1 expression, and interference with immunological synapse formation stemcell.com. Specifically, this compound may induce surface GM1 ganglioside on Bcr/Abl transfectants, which can prevent the proper redistribution of MHC-related antigen molecules in lipid rafts, thus hindering NK cell interaction stemcell.com. Additionally, this compound can affect cell surface glycosylation and decrease the expression of MHC-related antigens-A/B and UL-16-binding proteins on Bcr/Abl transfectants, thereby inhibiting the NKG2D activating pathway and NK-mediated cytolysis stemcell.com.

Despite these complexities, certain reports indicate that this compound can upregulate the expression of various activating receptors on NK cells, including NCR and NKG2D, and may enhance interferon-gamma (IFN-γ) release, thereby contributing to antitumor responses mdpi.com. This compound has also been shown to increase the surface expression of CXCR4, a chemokine receptor, on NK cells and monocytes in patients receiving the drug for CML, while reducing CXCR3 expression in NK cells aai.orgresearchgate.net. These modulations in chemokine receptor repertoire can influence immune cell trafficking.

Here's a summary of this compound's observed effects on NK cells:

LCK Kinase Inhibition

PDGFRα as a Molecular Target

Platelet-Derived Growth Factor Receptor alpha (PDGFRα) has been identified as a significant molecular target for this compound mesylate in osteosarcoma plos.orgnih.govnih.govresearchgate.net. Studies utilizing a phospho-receptor tyrosine kinase array kit have revealed PDGFRα as one of the main molecular targets for this compound mesylate, alongside other receptors such as PDGFRβ, Axl, RYK, EGFR, EphA2, EphA10, and IGF1R plos.orgnih.govresearchgate.netresearchgate.net. The functional activity of PDGFR in osteosarcoma cells (human MG-63, HOS; murine POS-1, MOS-J) has been confirmed through investigations of PDGF-BB induced signaling plos.orgnih.gov. This compound mesylate, at a concentration of 25 µM, markedly inhibited the PDGF-BB induced phosphorylation cascades of both PDGFRα and PDGFRβ, confirming their roles as functional targets in osteosarcoma plos.orgnih.gov. PDGFRα expression has been observed frequently (79.6%) in osteosarcoma patient surgical specimens and correlated with inferior event-free survival, highlighting its potential as a prognostic marker and therapeutic target nih.gov.

Table 1: PDGFRα and PDGFRβ Expression in Osteosarcoma Patients

Inhibition of AKT/mTOR Signaling Pathway

This compound mesylate has demonstrated its ability to inhibit the AKT/mTOR signaling pathway in osteosarcoma cells plos.orgnih.gov. In both human (HOS) and mouse (MOS-J) osteosarcoma cell lines, this compound mesylate effectively inhibited the phosphorylation of mTOR and Akt, key components of this pathway plos.orgnih.gov. This inhibition contributes to the observed anti-proliferative effects of this compound in osteosarcoma cells, leading to a G0/G1 cell cycle arrest in most cell lines and inducing cell death nih.gov. The suppression of the PI3K/AKT/mTOR pathway by this compound has significant implications as its dysregulated activation contributes to cell survival and proliferation in various cancers researchgate.net.

Activation of ERK1/2 Phosphorylation

Beyond inhibiting pro-survival pathways, this compound mesylate also activates ERK1/2 phosphorylation in osteosarcoma cells plos.orgnih.gov. While this compound inhibits the PDGF-BB induced phosphorylation of PDGFRα and PDGFRβ, it also significantly reduces the PDGF-BB induced phosphorylation of Akt and ERK1/2, indicating a complex modulation of downstream signaling pathways plos.orgnih.govspandidos-publications.com. This dual effect, inhibiting certain pro-proliferative pathways while activating others, underscores the intricate mechanistic actions of this compound.

Antifibrotic Mechanisms

This compound acts as a potent antifibrotic agent by simultaneously targeting two major profibrotic pathways: the c-Abl kinase and the Platelet-Derived Growth Factor Receptor (PDGFR) smw.chuzh.choup.comnih.gov. The c-Abl tyrosine kinase is an important downstream signaling molecule of transforming growth factor beta (TGF-β), a key mediator of fibrosis oup.comnih.gov. This compound binds competitively to the ATP-binding pocket of c-Abl, effectively blocking its tyrosine kinase activity oup.com. In cells deficient for c-Abl, the induction of extracellular matrix (ECM) proteins by TGF-β is significantly decreased oup.com.

In experimental models, this compound has been shown to efficiently inhibit the development of bleomycin-induced dermal fibrosis and also reduce established fibrosis smw.chuzh.chresearchgate.net. It prevents the differentiation of resting fibroblasts into myofibroblasts and reduces the synthesis and accumulation of extracellular matrix in lesional skin smw.chuzh.ch. Studies have demonstrated that this compound, at pharmacologically relevant concentrations, inhibits the synthesis of collagen 1a1, collagen 1a2, and fibronectin-1 in SSc fibroblasts by up to 90% smw.choup.comresearchgate.net. Furthermore, this compound abrogates the stimulation of fibrotic gene expression, including fibronectin, connective tissue growth factor, plasminogen activator inhibitor-1, and tissue inhibitor of metalloproteinases, induced by TGF-β nih.gov. This broad inhibition of profibrotic mediators positions this compound as a promising compound for managing fibrotic diseases.

Table 2: Antifibrotic Effects of this compound on ECM Protein Synthesis in SSc Fibroblasts

Modulation of Fibroblast Proliferation and Migration

This compound has been shown to significantly inhibit the proliferation and migration of fibroblasts, which are critical processes in the development and progression of fibrosis. Studies have demonstrated that this compound dose-dependently inhibits the growth of lung fibroblasts and their DNA synthesis, particularly when stimulated by Platelet-Derived Growth Factor (PDGF) atsjournals.org. For instance, this compound treatment at concentrations as low as 0.1 to 0.3 µM effectively suppressed proliferative responses in NIH3T3 and primary lung fibroblasts stimulated by PDGF-AA and PDGF-BB atsjournals.org. However, it did not significantly affect proliferation stimulated by epidermal growth factor (EGF) or fibroblast growth factor 2 (FGF-2) atsjournals.org.

In human breast stromal fibroblasts, this compound inhibits proliferation by blocking the activation of the extracellular signal-regulated kinase (ERK) and Akt signaling pathways and by up-regulating the cyclin-dependent kinase inhibitor p21WAF1, leading to cell cycle arrest at the G0/G1 phase aacrjournals.orgnih.gov. The inhibition of PDGF-mediated fibroblast proliferation was found to be more potent and primarily due to the inhibition of the Akt pathway aacrjournals.orgnih.gov.

Furthermore, this compound has been observed to impair profibrogenic cytokine-induced human pulmonary fibroblast migration in vitro nih.gov. For example, 1 µM this compound reduced the percentage of migrated normal human pulmonary fibroblasts stimulated by EGF and PDGF-AB, and this reduction became more pronounced at higher concentrations (e.g., 51.6% reduction at 10 µM) nih.gov. This suggests that this compound acts as a potential and specific inhibitor of fibroblast accumulation in fibrotic conditions nih.gov. In addition, this compound treatment impaired the migration of both pericytes and fibroblasts, with PDGF-BB identified as a major serum factor promoting this migration researchgate.net.

Table 1: Effect of this compound on Fibroblast Proliferation and Migration

Myofibroblast Differentiation Pathways

Myofibroblasts are key effector cells in fibrosis, characterized by increased ECM production and contractile properties. This compound has demonstrated the ability to prevent the differentiation of resting fibroblasts into myofibroblasts nih.govuzh.ch. In preclinical models of systemic sclerosis (SSc), such as the tight skin 1 (TSK-1) mouse model, this compound treatment reduced dermal and hypodermal thickening and prevented this critical transition nih.govuzh.ch.

While this compound can suppress transforming growth factor-beta (TGF-β)-induced myofibroblast differentiation through SMAD-independent pathways when administered during the injury phase, some studies suggest that it might not significantly affect the stably differentiated myofibroblast phenotype or epithelial-mesenchymal transition (EMT) if administered during the post-injury reparation phase researchgate.net. This implies a temporal sensitivity to this compound's antifibrotic effects, being more effective in early fibrogenic processes researchgate.netnih.gov.

Preclinical studies have also shown that this compound treatment can lead to a decrease in type I collagen and fibronectin-1 synthesis by both dermal fibroblasts and myofibroblasts nih.govoup.com. This reduction in ECM protein synthesis is a crucial aspect of its antifibrotic action.

Table 2: this compound's Impact on Myofibroblast Differentiation and ECM Production

Inhibition of c-Abl and PDGFR Tyrosine Kinases in Fibrogenesis

A cornerstone of this compound's antifibrotic mechanism lies in its potent and specific inhibition of c-Abl (Abelson kinase) and Platelet-Derived Growth Factor Receptor (PDGFR) tyrosine kinases atsjournals.orgnih.govnih.govahajournals.orgsmw.chersnet.orgatsjournals.orgnih.govresearchgate.nettandfonline.com. These tyrosine kinases play central roles in promoting fibrogenesis.

The c-Abl kinase, a non-receptor tyrosine kinase, is a significant downstream target of pro-fibrotic Transforming Growth Factor-beta (TGF-β) signaling oup.comsmw.ch. TGF-β is a central mediator in pro-fibrotic diseases, and its induction of extracellular matrix proteins is markedly reduced in cells deficient for c-Abl oup.comsmw.ch. This compound effectively blocks the tyrosine kinase activity of c-Abl, thereby interfering with TGF-β's pro-fibrotic effects nih.govnih.govoup.comahajournals.orgsmw.chnih.gov. For example, in experimental models, this compound abrogated the TGF-β-induced stimulation of Type I collagen production and other fibrotic gene products like fibronectin, connective tissue growth factor, and plasminogen activator inhibitor-1 nih.gov. It also reduced basal collagen gene expression in SSc fibroblasts nih.gov.

Simultaneously, this compound suppresses the tyrosine kinase activity of the PDGFR atsjournals.orgnih.govnih.govahajournals.orgsmw.chersnet.orgatsjournals.orgnih.govresearchgate.nettandfonline.com. PDGF can directly stimulate fibroblasts to contract collagen matrices and differentiate into myofibroblasts, and it also upregulates the expression of TGF-β1 and c-Abl in fibroblasts ahajournals.org. By inhibiting PDGFR, this compound blocks a major pro-fibrotic pathway that stimulates fibrogenesis and enhances fibroblast contractility smw.ch. Studies in rat cardiac fibroblasts have shown that this compound reduces collagen production by inhibiting the phosphorylation of both c-Abl and PDGFR-β, particularly under co-incubation with PDGF-BB and TGF-β1 ahajournals.org.

The combined inhibition of c-Abl and PDGFR by this compound is considered critical for its antifibrotic effects uzh.chersnet.orgresearchgate.net. This dual targeting mechanism allows this compound to disrupt multiple interdependent pathways that drive fibrosis, including the production of extracellular matrix and the contractility of fibroblasts oup.comsmw.ch. In models of radiation-induced fibrosis, this compound not only reduced the activation of PDGFR-β and c-Abl but also decreased the levels of TGF-β, suggesting an interruption of cross-talk between these pathways nih.gov.

Table 3: Key Tyrosine Kinase Targets of this compound in Fibrogenesis

Affinity Purification with Immobilized Kinase Inhibitors

Affinity purification, particularly using immobilized kinase inhibitors, is a prominent chemical proteomics strategy to identify direct cellular targets of kinase-selective drugs like this compound. This method involves using a resin to which non-selective kinase inhibitors are covalently attached. When cell lysates are passed over this resin, protein kinases that can bind to the inhibitors are retained. By comparing the proteins bound to the resin from untreated cells versus this compound-treated cells, researchers can identify kinases whose binding is affected by this compound, thus revealing potential direct targets or off-targets.

A proof-of-concept proteomics study applied this strategy to chronic myeloid leukemia cells expressing the Bcr-Abl fusion kinase. This integrated approach indicated additional this compound target candidates, such as flavine adenine dinucleotide synthetase, as well as repressed phosphorylation events on downstream effectors not yet implicated in this compound-regulated signaling. These included activity-regulating phosphorylations on the kinases Btk, Fer, and focal adhesion kinase, which may qualify them as alternative target candidates in Bcr-Abl-driven oncogenesis.

SILAC-based Quantitative Proteomics

Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) is a robust quantitative proteomics technique widely used to measure global protein expression changes and identify perturbed biological pathways in response to drug treatment. In SILAC, cells are metabolically labeled with "light" or "heavy" isotopic forms of amino acids, allowing for the precise quantification of protein abundance differences between treated and untreated samples via mass spectrometry.

SILAC has been instrumental in dissecting this compound's effects on the proteome of K562 human chronic myeloid leukemia cells, which express the Bcr-Abl fusion kinase. For instance, studies have shown that this compound treatment leads to significant alterations in the expression levels of numerous proteins. One study quantified 1344 proteins, finding 73 that had significantly altered levels of expression induced by this compound and could be quantified in both forward and reverse SILAC labeling experiments. These included the down-regulation of thymidylate synthase, S-adenosylmethionine synthetase, and glycerol-3-phosphate dehydrogenase, as well as the up-regulation of poly(ADP-ribose) polymerase 1, hemoglobins, and enzymes involved in heme biosynthesis. Furthermore, this compound-induced hemoglobinization and erythroid differentiation in K562 cells were found to be associated with global histone H4 hyperacetylation. These results provided potential biomarkers for monitoring therapeutic intervention of CML using this compound and offered new knowledge for gaining insight into its molecular mechanisms of action.

Another study utilized SILAC to compare proteome changes induced by this compound and novel this compound derivatives in K562 cells, quantifying a total of 986 proteins. This approach allowed for the identification of significantly altered proteins upon treatment with these compounds.

Table 1: Examples of Proteins with Altered Expression or Binding in K562 Cells Upon this compound Treatment (Proteomics Approaches)

Gene Expression Profiling and Network Analysis (e.g., Weighted Gene Co-expression Network Analysis (WGCNA))

Gene expression profiling, often performed using microarray or RNA sequencing, allows for the identification of differentially expressed genes (DEGs) in response to this compound treatment or in this compound-resistant cells. Subsequent network analysis, including Weighted Gene Co-expression Network Analysis (WGCNA), helps to uncover modules of highly correlated genes and identify hub genes that may play crucial roles in disease progression or drug response.

In the context of this compound research, gene expression profiling has revealed important insights into resistance mechanisms and disease pathways. Studies comparing this compound-sensitive and this compound-resistant K562 cells have identified hundreds of DEGs. Pathway enrichment analyses of these DEGs have highlighted their involvement in processes such as cell adhesion, cell migration, differentiation, inflammatory response, and signaling pathways like Rap1, focal adhesion, and those regulating pluripotency of stem cells.

WGCNA has been applied to analyze gene expression profiles from this compound-treated CML patients to identify immune-related genes (IRGs) associated with treatment response. This analysis categorized patients into high- and low-immune score groups and identified 428 differentially expressed IRGs. Functional enrichment analysis revealed that these genes were involved in immune-related pathways, including T-cell receptor signaling and cytokine-cytokine receptor interaction. Based on five modules in WGCNA and top-ranked degree, 10 hub genes were identified, with IL10RA, SCN9A, and SLC26A11 identified as potential biomarkers for predicting this compound response. For instance, high expression of IL10RA and SLC26A11, and low expression of SCN9A, were observed in responders.

WGCNA has also been used to explore this compound's effects in other conditions, such as rheumatoid arthritis, where it helped identify CSF1R as a core gene involved in inflammation that this compound could mitigate by suppressing its expression.

Mathematical Modeling of Immune Response Dynamics

Mathematical modeling plays a crucial role in understanding the complex dynamics of the immune system in chronic myeloid leukemia (CML) and its interaction with this compound therapy. These models often employ systems of differential equations to simulate the interplay between healthy cells, leukemic cells, and various immune cell populations.

Early mathematical models of CML dynamics under this compound treatment often did not incorporate the anti-leukemia immune response. However, recent experimental data indicating that this compound treatment may promote the development of anti-leukemia immune responses as patients enter remission have led to the development of more comprehensive models. These models, often utilizing delay differential equations to account for the duration of cell division, suggest that anti-leukemia T cell responses may play a critical role in maintaining CML patients in remission under this compound therapy. Furthermore, models propose that this compound therapy might drive leukemic cell populations to enter and fall below an "optimal load zone" too rapidly to sustain the anti-leukemia T cell response, suggesting vaccination approaches in combination with this compound could help sustain this response for a durable cure.

More recent mathematical models have delved into the intricacies of this compound's impact on specific T cell subsets, such as T helper (Th) cells and Treg cells, and their potential role in allergic reactions induced by the drug. These models integrate cellular interactions, drug pharmacokinetics, and immune responses to unveil mechanisms underlying the dominance of Th2 over Th1 and Treg cells, leading to allergic manifestations. Such models can also explore how this compound affects the maturation and functioning of Antigen-Presenting Cells (APCs) and, consequently, T cells within the immune system.

Table 2: Key Cellular Populations and Interactions Modeled in this compound-Immune Dynamics