N-(2-chloro-6-methylphenyl)-2-({6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl}amino)-1,3-thiazole-5-carboxamide

• ChemBase编号: 1123
• 分子式: C22H26ClN7O2S
• 平均质量: 488.00554
• 单一同位素质量: 487.15572179
• SMILES: Clc1c(NC(=O)c2sc(Nc3nc(nc(N4CCN(CC4)CCO)c3)C)nc2)c(ccc1)C
• Canonical SMILES: OCCN1CCN(CC1)c1cc(nc(n1)C)Nc1ncc(s1)C(=O)Nc1c(C)cccc1Cl
• 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)
• InChIKey: ZBNZXTGUTAYRHI-UHFFFAOYSA-N

名称和登记号

名称

• IUPAC标准名: N-(2-chloro-6-methylphenyl)-2-({6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl}amino)-1,3-thiazole-5-carboxamide
• IUPAC传统名: dasatinib
• 商标名: Sprycel
• 别名: dasatinib; BMS-354825; Dasatinib; Sprycel; BMS354825; N-[2-Chloro-6-methylphenyl]-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide

登记号

• CAS号: 302962-49-8
• MDL号: MFCD11046566
• PubChem SID: 160964586; 46505143
• PubChem CID: 3062316

理论计算性质

JChem

• Acid pKa: 8.516064
• 质子受体: 8
• 质子供体: 3
• LogD (pH = 5.5): 1.7241017
• LogD (pH = 7.4): 3.7472725
• Log P: 3.826838
• 摩尔折射率: 133.0762 cm^3
• 极化性: 48.7593 Å^3
• 极化表面积: 106.51 Å^2
• 可自由旋转的化学键: 7
• 里宾斯基五规则: true

ALOGPS 2.1

• Log P: 2.77
• LOG S: -4.58
• 溶解度: 1.28e-02 g/l

分子性质

理化性质

• 溶解度: 0.0128 mg/mL [Predicted by ALOGPS]; DMSO; Methanol
• 外观: White to Off-White Solid
• 熔点: 275-286°C
• 疏水性(logP): 1.8

安全信息

• 保存条件: -20°C; -20°C Freezer
• 保存注意事项: IRRITANT
• TSCA收录: false

药理学性质

• 作用靶点: Bcr-Abl; c-Kit; SRC

产品相关信息

• 纯度: 95+%; 98%
• 成盐信息: Free Base

详细说明

DrugBank - DB01254

• Drug Groups: approved; investigational
• Description: Dasatinib is an oral dual BCR/ABL and Src family tyrosine kinase inhibitor approved for use in patients with chronic myelogenous leukemia (CML). The main targets of Dasatinib, are BCRABL, SRC, Ephrins and GFR.
• Indication: For the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia with resistance or intolerance to prior therapy. Also indicated for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy.
• Pharmacology: Dasatinib is an oral dual BCR/ABL and Src family tyrosine kinase inhibitor
• Toxicity: Acute overdose in animals was associated with cardiotoxicity.
• Affected Organisms: Humans and other mammals
• Biotransformation: Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4
• Half Life: The overall mean terminal half-life of dasatinib is 3-5 hours.
• Protein Binding: 96%
• Elimination: Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4. Elimination is primarily via the feces.
• Distribution: * 2505 L
• References: Das J, Chen P, Norris D, Padmanabha R, Lin J, Moquin RV, Shen Z, Cook LS, Doweyko AM, Pitt S, Pang S, Shen DR, Fang Q, de Fex HF, McIntyre KW, Shuster DJ, Gillooly KM, Behnia K, Schieven GL, Wityak J, Barrish JC: 2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor. J Med Chem. 2006 Nov 16;49(23):6819-32. [Pubmed] ; Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, O'Brien S, Nicaise C, Bleickardt E, Blackwood-Chirchir MA, Iyer V, Chen TT, Huang F, Decillis AP, Sawyers CL: Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006 Jun 15;354(24):2531-41. [Pubmed]
• External Links: Wikipedia; RxList; Drugs.com

Selleck Chemicals - S1021

Research Area

• Description: Cancer,Non-Hodgkin's lymphoma

Biological Activity

• Description: Dasatinib (BMS-354825, Sprycel) is a Src/Abl inhibitor for wild type Abl and Src with IC50 of 0.6 nM and 0.8 nM, respectively.
• Targets:

  Wild type Abl

  ;

  Src

• IC50:

  0.6 nM

  ;

  0.8 nM ^[1]

• In Vitro: Dasatinib is more effective than imatinib in inhibiting the proliferation of Ba/F3 cells expressing wild-type Bcr-Abl and Bcr-Abl mutants, with the exception of T315I. Dasatinib has a two-log (～325-fold) increased potency relative to imatinib. Dasatinib potently inhibits wild-type Abl kinase and all mutants except T315I over a narrow range. Dasatinib directly targets wild-type and mutant Abl kinase domains and inhibits autophosphorylation and substrate phosphorylation in a concentration-dependent manner. Dasatinib displays 325-fold greater potency compared with imatinib against cells expressing wild-type Bcr-Abl. ^[1] The percent of colonies of TgE bone marrow cells are decreased from 100% in untreated wells to 4.12% in Dasatinib treated wells. In the presence of Dasatinib, the difference in the percentage of colonies formed by WT and TgE bone marrow cells is statistically significant. Expression of LMP2A is able to promote B lymphocyte survival and proliferation, which can be inhibited by targeting Lyn and/or c-Abl kinases through Dasatinib. ^[2] Dasatinib treatment inhibits Src signaling, decreases growth, and induces cell cycle arrest and apoptosis in a subset of thyroid cancer cells. Treatment with increasing doses of Dasatinib (0.019 μM to 1.25 μM) for 3 days inhibits the growth of the C643, TPC1, BCPAP, and SW1736 cell lines by about 50% at low nanomolar concentrations, while higher concentrations are required to inhibit the growth of the K1 cell line. Treatment with 10 nM or 50 nM Dasatinib results in a 9-22% increase of cells in the G1 population among BCPAP and SW1736 and K1 cells, and a corresponding 7-18% decrease in the percentage of cells in the S phase. ^[3]
• In Vivo: Dasatinib reverses splenomegaly in LMP2A/MYC double transgenic mice. Dasatinib specifically prevents colony formation by LMP2A expressing bone marrow B cells and decreased spleen size in the TgE mice. Spleen mass is significantly decreased among Dasatinib treated Tg6/λ-MYC mice when compared to the control group. Dasatinib inhibits lymphadenopathy in LMP2A/MYC double transgenic mice. Dasatinib reverses splenomegaly in Rag1KO mice engrafted with tumor cells from LMP2A/MYC double transgenic mice. Dasatinib therapy inhibits Lyn phosphorylation in B lymphocyte tumors expressing LMP2A. ^[2]
• Clinical Trials: Dasatinib has entered in a phase II clinical trial in the treatment of hemangiopericytoma and gastrointestinal stromal tumor.

Combination Therapy

• Description: Dasatinib significantly inhibits oesophageal carcinoma cell invasion and up-regulation of MAD2 (mitotic arrest-deficient 2), as well as inducing cell apoptosis and cell-cycle arrest. Additive and synergistic interactions are observed when Dasatinib is used in combination with docetaxel. ^[4] Dasatinib plus Decitabine has entered in a phase II clinical trial in the treatment of leukemia.

Protocol

• Protocol: Kinase Assay ^[1]
• Kinase autophosphorylation assays: Kinase assays using wild-type and mutant glutathione S-transferase (GST)-Abl fusion proteins (c-Abl amino acids 220-498) are done. GST-Abl fusion proteins are released from glutathione-Sepharose beads before use; the concentration of ATP is 5 μM. Immediately before use in kinase autophosphorylation and in vitro peptide substrate phosphorylation assays, GST-Abl kinase domain fusion proteins are treated with LAR tyrosine phosphatase. After 1-hour incubation at 30 °C, LAR phosphatase is inactivated by addition of sodium vanadate (1 mM). Immunoblot analysis comparing untreated GST-Abl kinase to dephosphorylated GST-Abl kinase is routinely done using phosphotyrosine-specific antibody 4G10 to confirm complete (>95%) dephosphorylation of tyrosine residues and c-Abl antibody CST 2862 to confirm equal loading of GST-Abl kinase. The Dasatinib concentration range is extended to 1,000 nM for mutant T315I. These same inhibitor concentrations are used for the in vitro peptide substrate phosphorylation assays. The three inhibitors are tested over these same concentration ranges against GST-Src kinase and GST-Lyn kinase.
• Protocol: Cell Assay ^[1]
• Cell Lines: Ba/F3 cell lines
• Concentrations: ~32 nM
• Incubation Time: 72 hours
• Methods:

  Ba/F3 cell lines are seeded in triplicate and incubated with escalating concentrations of Dasatinib for 72 hours. Proliferation is measured using a methanethiosulfonate-based viability assay. IC50 and IC90 values are reported as the mean of three independent experiments done in quadruplicate. The inhibitor concentration ranges are 0 nM to 32 nM (Dasatinib). The Dasatinib concentration range is extended to 200 nM for mutant T315I.

• Protocol: Animal Study ^[2]
• Animal Models: EμLMP2A (TgE and Tg6 strains), MYC (λ-MYC), and LMP2A/λ-MYC double transgenic mice (Tg6/λ-MYC)
• Formulation: DMSO
• Doses: 30 mg/kg
• Administration: Administered via i.p.

References

• References: [1] O'Hare T, et al. Cancer Res. 2005, 65(11), 4500-4505.
• References: [2] Dargart JL, et al. Antiviral Res. 2012, 95(1), 49-56.
• References: [3] Chan CM, et al. Clin Cancer Res. 2012, 18(13), 3580-3591
• References: [4] Wang L, et al. Clin Sci (Lond). 2012, 122(1), 13-24.

Toronto Research Chemicals - D193600

A new, oral, small-molecule Tyrosine Kinase Inhibitor (TKI) for the treatment of CML. Antineoplastic.

参考文献

• Das J, Chen P, Norris D, Padmanabha R, Lin J, Moquin RV, Shen Z, Cook LS, Doweyko AM, Pitt S, Pang S, Shen DR, Fang Q, de Fex HF, McIntyre KW, Shuster DJ, Gillooly KM, Behnia K, Schieven GL, Wityak J, Barrish JC: 2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor. J Med Chem. 2006 Nov 16;49(23):6819-32. Pubmed
• Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, O'Brien S, Nicaise C, Bleickardt E, Blackwood-Chirchir MA, Iyer V, Chen TT, Huang F, Decillis AP, Sawyers CL: Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006 Jun 15;354(24):2531-41. Pubmed
• O'Hare T, et al. Cancer Res. 2005, 65(11), 4500-4505.
• Dargart JL, et al. Antiviral Res. 2012, 95(1), 49-56.
• Chan CM, et al. Clin Cancer Res. 2012, 18(13), 3580-3591
• Wang L, et al. Clin Sci (Lond). 2012, 122(1), 13-24.
• Lombardo, L.J., et al: J. Med. Chem., 47, 6658 (2004)
• Shah, N. P., et al.: Science, 305, 399 (2004)
• O’Hare, T., et al.: Curr. Opin. Genet. Dev., 16, 92 (2004)