Nam, Yunju Hwang, Dongkeun Kim, Namdoo Seo, Hong-Seog Selim, Khalid B. Sim, Taebo 2024-01-19T21:02:31Z 2024-01-19T21:02:31Z 2021-09-05 2019-01-01 1475-6366 https://pubs.kist.re.kr/handle/201004/120485 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. English TAYLOR & FRANCIS LTD ANAPLASTIC LYMPHOMA KINASE DRUG-RESISTANT MUTANTS ALK INHIBITOR LUNG-CANCER PHARMACOLOGICAL EVALUATION BIOLOGICAL EVALUATION DUAL INHIBITORS FUSION GENE DISCOVERY DESIGN Identification of 1H-pyrazolo[3,4-b]pyridine derivatives as potent ALK-L1196M inhibitors Article 10.1080/14756366.2019.1639694 1 JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, v.34, no.1, pp.1426 - 1438 JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY 34 1 1426 1438 scie scopus 000480544200001 2-s2.0-85070969617 Biochemistry & Molecular Biology Chemistry, Medicinal Biochemistry & Molecular Biology Pharmacology & Pharmacy Article ANAPLASTIC LYMPHOMA KINASE DRUG-RESISTANT MUTANTS ALK INHIBITOR LUNG-CANCER PHARMACOLOGICAL EVALUATION BIOLOGICAL EVALUATION DUAL INHIBITORS FUSION GENE DISCOVERY DESIGN Anaplastic lymphoma kinase ALK-L1196M mutant pyrazolopyridine-based inhibitor