molecular formula C22H26ClN7O2S B193332 Dasatinib CAS No. 302962-49-8

Dasatinib

Cat. No.: B193332
CAS No.: 302962-49-8
M. Wt: 488.0 g/mol
InChI Key: ZBNZXTGUTAYRHI-UHFFFAOYSA-N
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Description

Dasatinib (Sprycel®) is a second-generation, orally administered tyrosine kinase inhibitor (TKI) approved for treating chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). It targets BCR-ABL1, SRC family kinases (SFKs), EPHA2, c-KIT, and PDGFR-β, among others . Its mechanism involves competitive inhibition of ATP-binding sites, blocking downstream signaling pathways critical for cancer cell proliferation and survival .

Pharmacokinetically, this compound exhibits rapid absorption (time to peak plasma concentration: 0.5–3 hours), a short half-life (~3–5 hours), and low systemic clearance, necessitating twice-daily dosing .

Properties

IUPAC Name

 N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide
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Description Data deposited in or computed by PubChem

InChI

 InChI=1S/C22H26ClN7O2S/c1-14-4-3-5-16(23)20(14)28-21(32)17-13-24-22(33-17)27-18-12-19(26-15(2)25-18)30-8-6-29(7-9-30)10-11-31/h3-5,12-13,31H,6-11H2,1-2H3,(H,28,32)(H,24,25,26,27)
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

InChI Key

 ZBNZXTGUTAYRHI-UHFFFAOYSA-N
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Canonical SMILES

 CC1=C(C(=CC=C1)Cl)NC(=O)C2=CN=C(S2)NC3=CC(=NC(=N3)C)N4CCN(CC4)CCO
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Molecular Formula

C22H26ClN7O2S
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

DSSTOX Substance ID

 DTXSID4040979
Record name Dasatinib
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Molecular Weight

488.0 g/mol
Source PubChem
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Description Data deposited in or computed by PubChem

Physical Description

Solid
Record name Dasatinib
Source Human Metabolome Database (HMDB)
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Description The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body.
Explanation HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications.

Solubility

1.28e-02 g/L
Record name Dasatinib
Source Human Metabolome Database (HMDB)
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CAS No.

 302962-49-8, 863127-77-9
Record name Dasatinib
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Record name Dasatinib [USAN:INN]
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Record name N-(2-chloro-6-methylphenyl)-2-({6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl}amino)-1,3-thiazole-5-carboxamide
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Record name Dasatinib
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Description The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body.
Explanation HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications.

Melting Point

280-286 °C, 280 - 286 °C
Record name Dasatinib
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Record name Dasatinib
Source Human Metabolome Database (HMDB)
URL http://www.hmdb.ca/metabolites/HMDB0015384
Description The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body.
Explanation HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications.

Preparation Methods

Core Synthetic Strategies for Dasatinib

The synthesis of this compound centers on constructing its thiazole-carboxamide-pyrimidine scaffold while introducing the critical 1-(2-hydroxyethyl)piperazine moiety. Two dominant synthetic routes have been industrialized, differentiated by their protection group strategies and coupling sequences.

Hydroxyl Protection-Directed Synthesis (Patented Route)

The method disclosed in US20130030177A1 employs a hydroxyl protection strategy to prevent undesired side reactions during the final coupling stage. This route proceeds through seven key stages:

  • Intermediate Formation : Reacting 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide with 4,6-dichloro-2-methylpyrimidine under basic conditions yields the dichloropyrimidine intermediate. Sodium amide (NaNH₂) facilitates this nucleophilic aromatic substitution at 60-80°C, achieving 85-90% conversion efficiency.

  • Hydroxyl Protection : The intermediate undergoes protection using benzyl, methoxymethyl, or methylthiomethyl groups. Benzyl protection (Pg = benzyl) demonstrates superior stability, with <2% deprotection observed during subsequent steps.

  • Piperazine Coupling : Protected intermediates react with 1-(2-hydroxyethyl)piperazine in acetonitrile using triethylamine (TEA) as base and tetrabutylammonium bromide (TBAB) as phase transfer catalyst. This dual catalytic system increases reaction rate by 40% compared to traditional methods.

  • Deprotection : Boron trichloride (BCl₃) in dichloromethane at -15°C cleanly removes benzyl groups without degrading the piperazine moiety. Post-deprotection purity reaches 98.3% before crystallization.

Critical Data :

ParameterBenzyl ProtectionMethoxymethylMethylthiomethyl
Yield (Coupling Step)64.7%70.6%80.7%
Final Purity98.3%99.8%99.6%
Deprotection Time5 h4 h3.5 h

This route's advantage lies in its adaptability to industrial scaling, with TBAB enabling efficient phase transfer in acetonitrile-water systems.

Monohydrate Crystallization Techniques

The US9145406B2 patent details an optimized process for this compound monohydrate production, addressing the compound's poor aqueous solubility (8 μg/mL). The crystallization protocol involves:

Solvent-Mediated Polymorph Control

  • Solvent System : Ethanol-water (4:1 v/v) at 75°C induces nucleation of monohydrate crystals

  • Cooling Profile : Linear cooling from 75°C to 30°C over 8 hours prevents anhydrate formation

  • Phase Purity : XRPD analysis confirms monohydrate signature peaks at 2θ = 6.8°, 13.5°, and 20.1°

DSC Characterization :

  • Endothermic peak at 123°C (water loss)

  • Melt decomposition at 298°C

  • Enthalpy of fusion: 152 J/g

Industrial batches using this method achieve 93-97% yield with HPLC purity >99.4%, surpassing pharmacopeial requirements.

Alternative Synthetic Approaches

Thiourea-Mediated Cyclization (Academic Route)

Chen et al. developed a three-stage synthesis starting from β-ethoxyacrylamide:

  • α-Bromination : NBS (N-bromosuccinimide) in CCl₄ introduces bromide at the α-position (82% yield)

  • Thiazole Formation : Reacting with thiourea derivative in ethanol/water (3:1) at reflux yields the thiazole core (74%)

  • Piperazine Coupling : HEP (2-(piperazin-1-yl)ethanol) in n-butanol at 110°C for 24 hours completes the synthesis

This route achieves 59% overall yield but requires stringent temperature control during the exothermic cyclization step.

Industrial Process Optimization

Comparative analysis of patented vs. academic methods reveals critical optimization parameters:

ParameterPatent US9145406B2Academic Route
Total Steps43
Overall Yield92-97%59%
Purity (HPLC)99.5-99.8%98.2%
Solvent Consumption15 L/kg28 L/kg
Process Time48 h72 h

The patented route's efficiency stems from:

  • TBAB Catalysis : Reduces reaction time from 36h to 20h

  • Water Modulation : Controlled addition (4mL/g) prevents emulsion formation

  • Crystallization Control : Ethanol-water anti-solvent system enhances crystal habit

Impurity Profiling and Control

Critical process-related impurities include:

  • N-Desmethyl this compound : Forms via demethylation during high-temperature steps (<0.15% in optimized processes)

  • Chloro Analogues : Result from incomplete coupling (controlled through TBAB-mediated phase transfer)

  • Oxidation Products : Minimized by nitrogen sparging during crystallization

Modern QC protocols employ UPLC-MS/MS to detect impurities at 0.01% levels, ensuring compliance with ICH Q3A guidelines.

Chemical Reactions Analysis

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.

Scientific Research Applications

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%.
StudyPopulationKey Findings
DASISIONNewly diagnosed CMLHigher MMR rates with this compound compared to imatinib
Long-term Follow-upCML patientsSustained cytogenetic responses over 11 years

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.

Mechanism of Action

Dasatinib exerts its effects by inhibiting multiple tyrosine kinases, including Bcr-Abl and the Src kinase family. It binds to the active and inactive conformations of the ABL kinase domain, preventing the phosphorylation and activation of downstream signaling pathways. This inhibition leads to the suppression of cell proliferation and induction of apoptosis in cancer cells .

Comparison with Similar Compounds

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 .

Biological Activity

Efficacy in Clinical Trials

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

Study Phase Population Dosage Major Findings
Phase I84 patients with CML and Ph+ ALL15 mg to 240 mg dailyResponses observed in all BCR-ABL genotypes except T315I mutation; reversible myelosuppression noted.
Phase II (START-A)174 CML patients in accelerated phase70 mg twice dailyMajor hematological response (MHR) in 64%; major cytogenetic response (MCgR) in 39%.
Phase III150 imatinib-resistant CML patients140 mg this compound vs. 800 mg imatinibThis compound showed superior MCgR rates; reduced treatment failure risk by 84%.

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.

Q & A

Basic Research Questions

Q. How can researchers assess the efficacy of dasatinib in vitro for solid tumor models?

Methodological Answer:

  • Use migration and invasion assays (e.g., Boyden chamber) to evaluate this compound's inhibitory effects on cancer cell motility .
  • Perform Western blotting to monitor phosphorylation status of Src, focal adhesion kinase (FAK), and downstream targets (e.g., paxillin, p130) to confirm pathway inhibition .
  • Conduct cell cycle analysis (flow cytometry) and apoptosis assays (Annexin V/PI staining) to quantify growth arrest and cell death .

Q. What molecular markers are commonly used to predict this compound sensitivity in preclinical studies?

Methodological Answer:

  • Baseline gene expression profiling (microarray/RNA-seq) of cancer cell lines to identify sensitivity signatures (e.g., six-gene model in breast/lung cancer) .
  • Validate markers via qRT-PCR or immunohistochemistry (IHC) for proteins like CAV-1, EphA2 (phospho-S897), and PTEN status .
  • Use reverse phase protein array (RPPA) to quantify pathway activation (MAPK, mTOR) linked to response .

Q. How does this compound affect T-cell activation in immunotherapy contexts?

Methodological Answer:

  • Isolate human CD3+ T cells or antigen-specific CD8+ T cells and treat with this compound ex vivo.
  • Measure cytokine production (ELISA for IL-2, IFNγ, TNFα), degranulation (CD107a/b mobilization), and activation (CD69 upregulation) .
  • Use carboxyfluorescein diacetate succinimidyl ester (CFSE) dilution assays to assess proliferation suppression .

Advanced Research Questions

Q. How can researchers resolve contradictions in predictive gene signatures for this compound response across studies?

Methodological Answer:

  • Perform multi-omics integration (genomic, transcriptomic, proteomic) to identify context-dependent biomarkers (e.g., tumor subtype, microenvironment) .
  • Validate signatures in orthotopic mouse models or patient-derived xenografts (PDXs) with clinical correlation .
  • Analyze failed clinical trials (e.g., phase II studies in triple-negative breast cancer) to refine inclusion criteria or combination strategies .

Q. What experimental approaches address this compound's off-target effects on non-cancer cells (e.g., immune suppression)?

Methodological Answer:

  • CRISPR/Cas9 screens to identify this compound targets in T cells (e.g., LCK, CSK) and validate using plasmid transfection/rescue experiments .
  • Compare dose-response curves between cancer cells and immune cells to optimize therapeutic windows .
  • Use phospho-specific flow cytometry to map signaling crosstalk (e.g., JAK-STAT vs. Src pathways) .

Q. How does cross-talk between EphA2 and BRaf/CRaf pathways influence this compound resistance?

Methodological Answer:

  • Co-immunoprecipitation and double immunofluorescence to detect BRaf/CRaf heterodimer disruption in CAV-1-high tumors .
  • Generate isogenic cell lines with EphA2 knockout (CRISPR) or BRaf mutations to test pathway dependency .
  • Use RPPA to correlate MAPK/mTOR pathway activation with drug resistance in vivo .

Q. What strategies enhance this compound's synergy with chemotherapy in ovarian cancer?

Methodological Answer:

  • Pre-screen cell lines for Src pathway activity (phospho-SRC IHC) and genomic Src signatures .
  • Use the Combination Index (CI) method: treat cells with this compound + carboplatin/paclitaxel, construct dose-response curves, and calculate CI values (CI < 1 indicates synergy) .
  • Validate in orthotopic models with longitudinal monitoring of tumor burden and metastasis .

Q. Data Contradiction Analysis

Q. Why do predictive gene signatures fail to translate into clinical benefit in some trials (e.g., metastatic breast cancer)?

Key Considerations:

  • Table: Comparison of Preclinical vs. Clinical Signature Performance
SignaturePreclinical Validation (Cell Lines)Clinical Trial Outcome (Phase II)
6-Gene Model92% sensitivity in breast cancerNot tested clinically
SRC Pathway Score83% accuracy in lung cancer0% response in marker-positive TNBC
  • Potential reasons: Tumor heterogeneity, stromal interactions, or compensatory pathways in vivo not modeled in vitro .

Q. How to interpret conflicting results between this compound's efficacy in leukemia vs. solid tumors?

Analysis Framework:

  • Compare BCR-ABL dependency in CML (primary target) vs. polypharmacology in solid tumors (e.g., Src, EphA2) .
  • Evaluate clinical trial designs: Leukemia studies often use biomarker-enriched cohorts (e.g., BCR-ABL mutations), whereas solid tumor trials lack selection criteria in early phases .

Q. Tables for Key Findings

Table 1. Clinically Tested Predictive Biomarkers for this compound

BiomarkerCancer TypeAssay PlatformClinical OutcomeReference
EphA2 (pS897)Uterine carcinomaIHC/RPPACorrelated with PFS in phase II
Triple-Negative SubtypeBreast cancerRNA-seqLimited single-agent activity
IL-8 SecretionCMLELISA/Serum AnalysisProposed early response marker

Table 2. Recommended In Vitro/In Vivo Models for this compound Studies

Model TypeApplicationKey Readouts
Orthotopic MiceMetastasis, pathway crosstalkTumor weight, phospho-protein IHC
PDX ModelsBiomarker validationEngraftment rate, drug response
3D Co-CultureStromal interaction effectsInvasion, cytokine secretion

Retrosynthesis Analysis

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Feasible Synthetic Routes

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Please be aware that all articles and product information presented on BenchChem are intended solely for informational purposes. The products available for purchase on BenchChem are specifically designed for in-vitro studies, which are conducted outside of living organisms. In-vitro studies, derived from the Latin term "in glass," involve experiments performed in controlled laboratory settings using cells or tissues. It is important to note that these products are not categorized as medicines or drugs, and they have not received approval from the FDA for the prevention, treatment, or cure of any medical condition, ailment, or disease. We must emphasize that any form of bodily introduction of these products into humans or animals is strictly prohibited by law. It is essential to adhere to these guidelines to ensure compliance with legal and ethical standards in research and experimentation.

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