Identification of 1H-pyrazolo[3,4-b]pyridine derivatives as potent ALK-L1196M inhibitors

Journal of Enzyme Inhibition and Medicinal Chemistry

Khalid B. Selim¹  Yunju Nam²  Dongkeun Hwang²  Hong-Seog Seo³  Taebo Sim⁴  Namdoo Kim⁵ 

[1] Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea;Department of Pharmaceutical Organic Chemistry, Mansoura University, Mansoura, Egyp;KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea;KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea;Cardiovascular Center, Korea University Guro Hospital, Seoul, Republic of Korea;KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea;Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea;NDBio Therapeutics Inc., Incheon, Republic of Korea;

关键词: Anaplastic lymphoma kinase;    ALK-L1196M mutant;    pyrazolopyridine-based inhibitor;   

DOI  :  10.1080/14756366.2019.1639694

来源: publisher

【 摘 要 】

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, 10g. 10g displayed exceptional enzymatic activities (<0.5 nM of IC50) against ALK-L1196M as well as against ALK-wt. In addition, 10g is an extremely potent inhibitor of ROS1 (<0.5 nM of IC50) and displays excellent selectivity over c-Met. Moreover, 10g 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, 10g 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.

【 授权许可】

CC BY