Dasatinib

Dasatinib Metabolism

This compound is primarily metabolized by CYP3A4 in humans, with minor contributions from flavin-containing monooxygenase 3 (FMO3) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes . Several metabolites have been identified :

• M4, M20, and M24: Mainly generated by CYP3A4 .
• M5: Generated by FMO3 .
• M6: Generated by a cytosolic oxidoreductase .

This compound Interactions with Kinases

This compound interacts with the ATP-binding cleft of various kinases, inhibiting their activity . Chemical proteomics have identified over 40 kinase targets of this compound .

• Direct Targets: ABL, ARG, SRC, LYN, YES, LCK, FRK, BRK (PTK6), ACK (TNK2), CSK, Ephrin receptors, DDR1, EGFR .
• Indirect Targets: FAK, CASL, paxillin, cortactin, and CDCP1 .

This compound Conjugation

To modulate this compound's properties, derivatives have been synthesized through esterification with amino acids and fatty acids . These modifications can affect the drug's stability and binding affinity . Modeling studies have shown that these chemical modifications are generally well-tolerated, with favorable binding energies .

Chemical Proteomics of this compound Targets

Chemical proteomics, using c-Dasatinib as bait, identified numerous kinases that interact with this compound . This approach helps to understand the wide-ranging effects of this compound on tyrosine kinases and identify both direct binding partners and downstream substrate proteins .

Effects on Tyrosine Kinase Activity

This compound inhibits the tyrosine kinase activity of its direct targets and induces changes in downstream substrate proteins . Studies using drug-resistant gatekeeper mutants have shown that SFK kinases, particularly SRC and FYN, as well as EGFR, are relevant targets for this compound action .

Treatment of Chronic Myeloid Leukemia (CML)

Dasatinib is approved for all phases of CML, particularly in patients who are newly diagnosed or have shown resistance to imatinib. Key studies demonstrate its effectiveness:

• Frontline Therapy : In the DASISION trial, this compound was compared with imatinib as a first-line treatment for newly diagnosed CML patients. Results showed that this compound led to higher rates of major molecular response (MMR) at 5 years (84% vs. 64% for imatinib) and improved progression-free survival .
• Long-term Efficacy : A long-term follow-up study indicated that this compound maintains a favorable safety profile while achieving high rates of cytogenetic responses. After 11 years, the cumulative complete cytogenetic response rate was 92.6%, and the major molecular response rate was 88.2% .

Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

This compound is also indicated for Ph+ ALL, particularly in cases where patients are resistant or intolerant to prior therapies. Its application in this context has been supported by clinical trials demonstrating significant efficacy in inducing remission .

Immunomodulatory Effects

Recent studies suggest that this compound may possess immunomodulatory properties beyond its role as a kinase inhibitor. Research has indicated potential benefits in enhancing immune responses, which could be leveraged in combination therapies for various malignancies .

Drug Repurposing

This compound's profile has led to investigations into its repurposing for other conditions. For instance, ongoing studies are exploring its effectiveness in solid tumors and other hematological malignancies due to its mechanism of action against multiple kinases involved in tumor progression .

Safety Profile

This compound is generally well-tolerated; however, it is associated with specific adverse effects such as pleural effusion, thrombocytopenia, and fatigue. The incidence of pleural effusion was notably higher during the first year of treatment . Long-term studies continue to monitor these effects, ensuring that the benefits outweigh the risks for patients.

ダサチニブは、Bcr-AblやSrcキナーゼファミリーなど、複数のチロシンキナーゼを阻害することで効果を発揮します。ABLキナーゼドメインの活性型と不活性型の両方に結合し、下流のシグナル伝達経路のリン酸化と活性化を阻害します。 この阻害は、癌細胞の増殖抑制とアポトーシス誘導につながります .

類似化合物:

イマチニブ： 同じような適応症に使用される別のチロシンキナーゼ阻害剤です。

ニロチニブ： ダサチニブに似ていますが、結合プロファイルが異なり、ダサチニブが効果を発揮しない場合に使用されます。

ボスチニブ： 活性スペクトルが異なる別のチロシンキナーゼ阻害剤です。

ユニークさ： ダサチニブは、ABLキナーゼドメインの活性型と不活性型の両方を阻害する、幅広いキナーゼを阻害する能力においてユニークです。 これは、イマチニブなどの他の阻害剤が耐性により効果を発揮できない場合に有効です .

Comparison with Similar Compounds

Efficacy Against Kinase Targets

Dasatinib demonstrates superior binding affinity compared to other TKIs. In molecular docking studies against ACK1, this compound achieved a Goldscore of 63.78 and Chemscore of −25.09, outperforming DBQ (a general kinase inhibitor) through hydrogen bonding with A208, E206, and S212 residues and hydrophobic interactions with T205 and D270 .

In DDR1 inhibition studies, this compound served as a positive control, achieving dose-dependent inhibition of auto-phosphorylation (IC₅₀ < 1 µM), comparable to novel compounds like "Compound 1" and "Compound 2" .

Structural Analogs and Derivatives

• Compound 6d: A this compound derivative with a modified pyrimidin-4-ylamino core. While it showed comparable antiproliferative activity in K563 leukemia cells (IC₅₀ similar to this compound), it was less effective in solid tumors (e.g., IC₅₀ = 20.2 µM in MCF-7 vs. This compound’s IC₅₀ < 1 µM), highlighting the critical role of this compound’s core structure in broad-spectrum efficacy .
• Quinoxaline-derivative 8b: Exhibited transcriptome effects similar to this compound in K562 cells, downregulating MYC and E2F targets. However, it uniquely inhibited oxidative phosphorylation and unfolded protein response pathways, suggesting divergent off-target effects .

Pharmacoeconomic Comparison

In a 40-year cost-effectiveness model, nilotinib (another second-generation TKI) outperformed this compound in CML treatment, yielding:

• +2.16 life-years and +1.89 QALYs (quality-adjusted life-years)
• Cost savings of €38,760 per patient due to prolonged treatment-free remission (TFR) .

Synergistic Combinations

• With IKKβ inhibitors: Co-administration with CmpdA enhanced caspase-3 cleavage and NF-κB inhibition in cisplatin-resistant HNSCC, surpassing monotherapy effects .
• With mTOR inhibitors: AZD2014 + this compound reduced metabolic activity in vestibular schwannoma cells at 0.1 µM, a physiologically achievable concentration .

Key Differentiators and Clinical Implications

• Dosing Flexibility : Despite its short half-life, this compound’s efficacy allows for intermittent dosing in combination therapies, reducing cumulative toxicity .
• Economic Limitations: While nilotinib is more cost-effective, this compound remains preferred in cases requiring rapid BCR-ABL1 inhibition or SFK targeting .

Dasatinib, a potent multikinase inhibitor, is primarily used in the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). This article delves into the biological activity of this compound, focusing on its mechanisms of action, efficacy in clinical trials, and its impact on various cellular pathways.

This compound targets multiple kinases involved in cancer progression. Its primary action is through the inhibition of the BCR-ABL fusion protein, which is responsible for the pathogenesis of CML. In addition to BCR-ABL, this compound inhibits several other kinases:

• SRC Family Kinases : SRC, LCK, HCK, YES, FYN, FGR, BLK, LYN.
• Receptor Tyrosine Kinases : c-KIT, PDGFR (α and β), DDR1 and 2.
• TEC Family Kinases : TEC and BTK.

This broad-spectrum activity allows this compound to overcome resistance mechanisms associated with imatinib treatment by effectively targeting most clinically relevant BCR-ABL mutations .

Efficacy in Clinical Trials

This compound has undergone extensive clinical evaluation across multiple phases. Below is a summary of key findings from significant studies:

Case Studies and Observations

• Case Study on Immunomodulatory Effects :
  • Recent studies indicate that this compound may activate anti-leukemic immune responses despite initial findings suggesting immunosuppressive effects. This dual role could enhance therapeutic efficacy while contributing to side effects observed during treatment .
• Neutrophil Function Inhibition :
  • This compound has been shown to inhibit integrin- and Fc-receptor-mediated functions in neutrophils. This inhibition occurs at low concentrations (IC50 < 10 nM), suggesting potential applications in inflammatory conditions where neutrophil activation plays a critical role .

Side Effects and Management

This compound treatment is associated with several side effects that can impact patient quality of life. The most common adverse events reported include:

• Diarrhea
• Fatigue
• Myelosuppression
• Pleural effusion

Management strategies involve monitoring blood counts regularly and adjusting dosages as necessary to mitigate severe side effects while maintaining therapeutic efficacy .