Bcr-Abl fusion tyrosine kinase is formed because of a reciprocal chromosomal translocation between chromosomes 9 and 22, producing the Philadelphia chromosome. Bcr-Abl is expressed in chronic myeloid leukemia(CML) and a chronic of acute lymphocytic leukemia[3]. GZD824 is an orally bioavailable inhibitor against a broad spectrum of Bcr-Abl mutants including Bcr-AblWT and Bcr-AblT315I with Kd values of 0.32nM and 0.71nM, respectively, and with IC50 values of 0.34nM and 0.68nM, respectively. In vitro, GZD824 potently suppressed proliferation of Bcr-Abl positive human CML cell lines K562 , Ku812, SUP-B15, U-937, MOLT4 and HL-60 with IC50 values of 0.2nM, 0.13nM, 2.5nM, 390.2nM, 26.3nM, and348.9nM, respectively. GZD824 suppressed the activation of Bcr-Abl and downstream Crk1 and STAT5 in a dose-dependent manner in K562 cells. In vivo, oral administration of GZD824 at 5 and 10mg/kg once daily for 14 consecutive days significantly suppressed tumor growth in mice bearing xenografted K562 cells. Oral administration of GZD824 at 1mg/kg once daily for 14 days induced complete tumor regression in mice bearing xenografted Ku812 cells. In addition, treatment of the mice bearing xenografted Ba/F3 cells expressing Bcr-Abl T315I with GZD824 at dose of 20mg/kg once daily via oral administration for 14 days induced almost complete tumor regression[1].
作用机制
GZD824 inhibits the activation of Bcr-Abl by binding to the ATP-binding site of nonphosphorylated(DGF-out) Bcr-Abl[1].
搜索
