Structure Based Drug Design of Crizotinib (PF-02341066), a Potent and Selective Dual Inhibitor of Mesenchymal-Epithelial Transition Factor (c-MET) Kinase and Anaplastic Lymphoma Kinase (ALK)
Structure Based Drug Design of Crizotinib (PF-02341066), a Potent and Selective Dual Inhibitor of Mesenchymal-Epithelial Transition Factor (c-MET) Kinase and Anaplastic Lymphoma Kinase (ALK)
复制标题
DOI：
10.1021/jm2007613
复制
发表时间：
2011-09-22
影响因子：
7.3
通讯作者：
Edwards, Martin P.
中科院分区：
文献类型：
--
作者：
Cui, J. Jean;Tran-Dube, Michelle;Edwards, Martin P.
由于异常信号传导在癌症中的关键作用，c-MET和ALK受体酪氨酸激酶都是治疗干预的有吸引力的肿瘤学靶点。与c-MET激酶结构域结合的3（PHA-665752）的共晶结构揭示了一种新的ATP位点环境，该环境可作为指导平行、多属性药物设计的靶标。为了更有效地实现与3的关键相互作用，设计了一个新的2-氨基-5-芳基-3-苄氧基吡啶系列。在新的系列中，2-氨基吡啶核心允许3-苄氧基通过更直接的载体进入与3的2，6-二氯苯基相同的口袋，因此具有更好的配体效率（LE）。对先导化合物系列的进一步优化产生了临床候选药物克唑替尼（PF-02341066），其在体外和体内均表现出强效的c-MET激酶和ALK抑制作用、有效的肿瘤生长抑制作用和良好的药物特性。
Because of the critical roles of aberrant signaling in cancer, both c-MET and ALK receptor tyrosine kinases are attractive oncology targets for therapeutic intervention. The cocrystal structure of 3 (PHA-665752), bound to c-MET kinase domain, revealed a novel ATP site environment, which served as the target to guide parallel, multiattribute drug design. A novel 2-amino-5-aryl-3-benzyloxypyridine series was created to more effectively make the key interactions achieved with 3. In the novel series, the 2-aminopyridine core allowed a 3-benzyloxy group to reach into the same pocket as the 2,6-dichlorophenyl group of 3 via a more direct vector and thus with a better ligand efficiency (LE). Further optimization of the lead series generated the clinical candidate crizotinib (PF-02341066), which demonstrated potent in vitro and in vivo c-MET kinase and ALK inhibition, effective tumor growth inhibition, and good pharmaceutical properties.