a KU-KIST Graduate School of Converging Science and Technology, Korea University , Seoul , Republic of Korea.
b NDBio Therapeutics Inc. , Incheon , Republic of Korea.
J Enzyme Inhib Med Chem. 2019 Dec;34(1):1426-1438. doi: 10.1080/14756366.2019.1639694.
Anaplastic lymphoma kinase (ALK) has been recognised as a promising molecular target of targeted therapy for NSCLC. We performed SAR study of pyrazolo[3,4-b]pyridines to override crizotinib resistance caused by ALK-L1196M mutation and identified a novel and potent L1196M inhibitor, . displayed exceptional enzymatic activities (<0.5 nM of IC) against ALK-L1196M as well as against ALK-wt. In addition, is an extremely potent inhibitor of ROS1 (<0.5 nM of IC) and displays excellent selectivity over c-Met. Moreover, strongly suppresses proliferation of ALK-L1196M-Ba/F3 and H2228 cells harbouring EML4-ALK via apoptosis and the ALK signalling blockade. The results of molecular docking studies reveal that, in contrast to crizotinib, engages in a favourable interaction with M1196 in the kinase domain of ALK-L1196M and hydrogen bonding with K1150 and E1210. This SAR study has provided a useful insight into the design of novel and potent inhibitors against ALK gatekeeper mutant.
间变性淋巴瘤激酶 (ALK) 已被认为是 NSCLC 靶向治疗的有前途的分子靶点。我们对吡唑并[3,4-b]吡啶进行了 SAR 研究，以克服由 ALK-L1196M 突变引起的克唑替尼耐药性，并鉴定出一种新型有效的 L1196M 抑制剂 。 对 ALK-L1196M 以及 ALK-wt 具有出色的酶活性（IC 低于 0.5 nM）。此外， 是一种极其有效的 ROS1 抑制剂（IC 低于 0.5 nM），对 c-Met 具有优异的选择性。此外， 通过凋亡和 ALK 信号阻断强烈抑制携带 EML4-ALK 的 ALK-L1196M-Ba/F3 和 H2228 细胞的增殖。分子对接研究的结果表明，与克唑替尼相比， 与 ALK-L1196M 激酶结构域中的 M1196 进行了有利的相互作用，并与 K1150 和 E1210 形成氢键。这项 SAR 研究为设计针对 ALK 门控突变体的新型有效抑制剂提供了有用的见解。
