9-(Arenethenyl)purines as Dual Src/Abl Kinase Inhibitors Targeting the Inactive Conformation: Design, Synthesis, and Biological Evaluation
9-(Arenethenyl)purines as Dual Src/Abl Kinase Inhibitors Targeting the Inactive Conformation: Design, Synthesis, and Biological Evaluation
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DOI：
10.1021/jm900166t
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发表时间：
2009-08-13
影响因子：
7.3
通讯作者：
Shakespeare, William C.
中科院分区：
文献类型：
--
作者：
Huang, Wei-Sheng;Zhu, Xiaotian;Shakespeare, William C.
一系列新的有效的双Src/Abl激酶抑制剂的基础上9-（arenethenyl）嘌呤核心已被确定。与靶向活性酶构象的传统双Src/Abl抑制剂不同，这些抑制剂结合到两种激酶的无活性DFG外构象。广泛的SAR研究发现了有效的口服生物可利用的抑制剂，其中一些在体内表现出疗效。抑制剂9 i（AP 24226）每日一次经口给药显著延长了以10 mg/kg剂量静脉注射表达野生型Bcr-Abl的Ba/F3细胞的小鼠的生存期。在一个单独的模型中，对携带表达NIH 3 T3细胞的Src Y 527 F皮下异种移植物的小鼠口服给予9 i引起剂量依赖性肿瘤缩小，在最高剂量下观察到完全肿瘤消退。值得注意的是，几种抑制剂（例如，14 a，AP 24163）对Bcr-Abl突变体T3151（一种对目前市售的所有慢性髓性白血病治疗均具有耐药性的变体）显示出适度的细胞效力（IC 50 = 300-400 nM）。
A novel series of potent dual Src/Abl kinase inhibitors based on a 9-(arenethenyl)purine core has been identified. Unlike traditional dual Src/Abl inhibitors targeting the active enzyme conformation, these inhibitors bind to the inactive, DFG-out Conformation of both kinases. Extensive SAR studies led to the discovery of potent and orally bioavailable inhibitors, some of which demonstrated in vivo efficacy. Once-daily oral administration of inhibitor 9i (AP24226) significantly prolonged the survival of mice injected intravenously with wild type Bcr-Abl expressing Ba/F3 cells at a dose of 10 mg/kg. In a separate model, oral administration of 9i to mice bearing subcutaneous xenografts of Src Y527F expressing NIH 3T3 cells elicited dose-dependent tumor shrinkage with complete tumor regression observed at the highest dose. Notably, several inhibitors (e,g., 14a, AP24163) exhibited modest cellular potency (IC50 = 300-400 nM) against the Bcr-Abl mutant T3151, a variant resistant to all currently marketed therapies for chronic myeloid leukemia.