生物活性

• 靶点

  Bcr-Abl IC50:5.8nM

  Lyn IC50:19nM

• 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. Bafetinib is dual Abl/Lyn inhibitor with IC50 values of 5.8nM and 19nM (measured by kinase activity), respectively. Further in vitro kinase assays showed that Bafetinib can inhibit almost all Bcr-Abl point mutants tested, including M244V, G250E, Q252H, Y253F, E255K, E255V, F317L, M351T, E355G, E359V, H396P and F486S at concentration ranging in 81-1400nM. Compared with imatinib, Bafetinib can block cellular autophosphorylation of Abl-wt, Bcr-Abl and its mutation E255K, but not T315I, at much lower concentration ranging in 11-340nM, whereas the inhibitory effect against PDGFR and c-Kit by Bafetinib was very similar to imatinib. Consistent with this, obvious dephosphorylation of the downstream mediators of Bcr-Abl or the mutant E255K, including p-CrkL and p-ERK by Bafetinib occurred at concentration of 0.1-10μM in cells, almost 10 fold less than imatinib. The anti-proliferative effect by Bafetinib can also observed at low micromolar concentration in Bcr-Abl–positive cell lines K562, KU812 and BaF3/wt. In vivo studies showed that Bafetinib can significantly inhibited tumor growth at dose of only 0.2 mg/kg/d, whereas dose at 20 mg/kg/d completely inhibited tumor growth without any adverse effects in Balb/c-nu/nu mice xenograft Bcr-Abl–positive KU812 cells, at least 10-fold more potent than imatinib. Bafetinib at dose of 60, 120 and 200mg/kg significantly prolonged the survival of the mice in a dose-dependent manner in Balb/c-nu/nu mice received BaF3/wt cells intravenously, while all mice treated with 400 mg/kg/d imatinib died by day 25^[1].
• 作用机制Bafetinib is an ATP non-competitive inhibitor.^[2]

• 动物研究
  剂量	Mice: min = 0.2 mg/kg, max = 20 mg/kg[1] (p.o.); 4 mg/kgWO2014039742A1 (i.p.) Rats: 30 mg/kg[4] (p.o.)
  给药途径	p.o., i.p.
  毒性数据 (半致死量)	Mice: MTD = 200 mg/kg p.o.[1]

• 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
  NCT00469534	High Grade Glioma	Not Applicable	Withdrawn	-	-
  NCT00352677	Chronic Myeloid Leukemia ... more >> Acute Lymphocytic Leukemia Collapse <<	Phase 1	Completed	-	United States, Florida ... more >> H. Lee Moffitt Cancer Center and Research Institute Tampa, Florida, United States, 33612 United States, Texas University of Texas MD Anderson Cancer Center Houston, Texas, United States, 77030 Germany Charite University of Medicine Berlin, Germany, 13353 Johann Wolfgang Goethe Universität Frankfurt am Main, Germany, 60590 University of Heidelberg Medical Clinic Mannheim, Germany, 68305 Israel Chaim Sheba Medical Center Tel Hashomer, Israel, 52621 Collapse <<
  NCT01215799	Hormone Refractory Prostate Ca... more >>ncer Collapse <<	Phase 2	Completed	-	United States, California ... more >> City of Hope Medical Center Duarte, California, United States, 91010 Collapse <<

• 更多
• 参考文献

• [1] Kimura S, Naito H, et al. NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia. Blood. 2005;106(12):3948-54.

  [2] Kimura S, Ashihara E, Maekawa T. New tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia. Curr Pharm Biotechnol. 2006;7(5):371-9.

  [3] WO2014039742A1

  [4] Kantarjian H, le Coutre P, et al. Phase 1 study of INNO-406, a dual Abl/Lyn kinase inhibitor, in Philadelphia chromosome-positive leukemias after imatinib resistance or intolerance. Cancer. 2010;116(11):2665-72.