生物活性

• 靶点

  Abl IC50:1nM

  c-Kit IC50:79nM

  c-Kit (D816V) IC50:37nM

  Src IC50:0.8nM

• 描述The oncogenic tyrosine kinase Bcr-Abl plays a central role in the pathogenesis of chronic myelogenous leukemia, thus makes it as the therapy drug target. However, it is demonstrated that the mutations of Bcr-Abl kinase have been the most common mechanism of drug resistance, such as imatinib. Dasatinib is a potent Bcr-Abl inhibitor with IC50 values of 0.6 nM, 0.8 nM and 2.8 nM for Abl, Src and Lyn, as well as IC50 values ranging in 0.1 - 1.8 nM for different Abl mutations except the T315l mutation (measured by in vitro kinase assays). Consistent with the results from the kinase assays, dasatinib showed more potent growth inhibition in Ba/F3 expressing various Abl mutations with a narrow range of low nanomoles, as well as the inhibition on Bcr-Abl tyrosine phosphorylation with IC50 values below 10 nM，compared with imatinib^[1] Oral administration of Dasatinib at dose of 5 or 20 mg/kg robustly reduced the CML phenotype and included stem and progenitor populations in tetracycline-controlled transgenic BCR-ABL mice, more potent than imatinib^[2]. Dasatinib also showed inhibitory activity against Lck, yes and c-kit with IC50 values of 0.4 nM, 0.5 nM and 5 nM, respectively, and possessed cellular antiproliferative activities on tumor cells of different origins, most potent to CML cell line K562 with IC50 < 1 nM. Oral treatment with Dasatinib, at dose of both 5 mg/kg and 50mg/kg on a 5 day on and 2 day off schedule for two cycles, demonstrated complete tumor regressions in a K562 xenograft model of CML^[3].
• 作用机制Dasatinib is a ATP-competitive inhibitor of both Abl and Src^[4].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  697	-	Growth Inhibition Assay	-	IC50=0.19987 μM	SANGER
  8-MG-BA	-	Growth Inhibition Assay	-	IC50=0.15458 μM	SANGER
  A101D	-	Growth Inhibition Assay	-	IC50=1.03043 μM	SANGER

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• 动物研究
  剂量	Mice[5]: 1.5 mg/kg (i.v.), 1.25 mg/kg - 5 mg/kg (p.o.)
  给药途径	i.v., p.o.
  动物药代数据	Animal Mice[6] Rats[6] Dogs[6] Monkeys[6] Dose 5 mg/kg 10 mg/kg 3 mg/kg 5 mg/kg Administration p.o. p.o. p.o. p.o. Cmax 0.051 μg/ml 0.24 ± 0.09 μg/ml 0.14 ± 0.04 μg/ml 0.17 ± 0.03 μg/ml T1/2 2.5 h 3.1 ± 0.3 h 5.0 ± 1.8 h 2.2 ± 0.4 h AUC0→∞ 0.22 μg·h/ml 1.9 ± 1.0 μg·h/ml 0.68 ± 0.17 μg·h/ml 0.37 ± 0.02 μg·h/ml F 0.17 27 ± 15 (%) 34 ± 13 (%) 15 ± 2 (%) Tmax 2 h 2.3 ± 3.3 h 0.75 ± 0.25 h 0.6 ± 0.1 h

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02546791	-	-	Completed	-	-
  NCT00339144	Tumors	Phase 1	Completed	-	Japan ... more >> Local Institution Osakasayama City, Osaka, Japan, 589-0014 Local Institution Koto-Ku, Tokyo, Japan, 135-0063 Collapse <<
  NCT01876953	Adult Acute Myeloid Leukemia W... more >>ith 11q23 (MLL) Abnormalities Adult Acute Myeloid Leukemia With Del(5q) Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) Adult Acute Myeloid Leukemia With t(15;17)(q22;q12) Adult Acute Myeloid Leukemia With t(16;16)(p13;q22) Adult Acute Myeloid Leukemia With t(8;21)(q22;q22) Recurrent Adult Acute Myeloid Leukemia Secondary Acute Myeloid Leukemia Untreated Adult Acute Myeloid Leukemia Collapse <<	Phase 1 Phase 2	Completed	-	United States, California ... more >> City of Hope Medical Center Duarte, California, United States, 91010 Collapse <<

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• 参考文献

• [1] O'Hare T, Walters DK, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 2005 Jun 1;65(11):4500-5.

  [2] Dasatinib Exerts Differential Effects on Normal and BCR-ABL Positive Hematopoietic Cells in a Transgenic Mouse Model of Chronic Phase-CML

  [3] Lombardo LJ, Lee FY, et al. Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem. 2004 Dec 30;47(27):6658-61.

  [4] Reddy EP, Aggarwal AK, et al. The ins and outs of bcr-abl inhibition. Genes Cancer. 2012 May;3(5-6):447-54.

  [5] Luo FR, Yang Z, et al. Dasatinib (BMS-354825) pharmacokinetics and pharmacodynamic biomarkers in animal models predict optimal clinical exposure. Clin Cancer Res. 2006 Dec 1;12(23):7180-6.

  [6] Pharmacokinetics of dasatinib

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