Open AccessDiscovery of CJ-2360 as a Potent and Orally Active Inhibitor of Anaplastic Lymphoma Kinase Capable of Achieving Complete Tumor Regression
Author(s) -
Jianyong Chen,
Yunlong Zhou,
Xuyuan Dong,
Liu Liu,
Longchuan Bai,
Donna McEachern,
Sally Przybranowski,
ChaoYie Yang,
Jeanne A. Stuckey,
Xiaoqin Li,
Bo Wen,
Ting C. Zhao,
Siwei Sun,
Duxin Sun,
Long Jiao,
Jing Yu,
Ming Guo,
Dajun Yang,
Shaomeng Wang
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c01550
Subject(s) - anaplastic lymphoma kinase , alk inhibitor , chemistry , ic50 , potency , kinase , lymphoma , enzyme inhibitor , cancer research , pharmacology , in vitro , biochemistry , medicine , pleural effusion , malignant pleural effusion
We report herein the discovery of a class of potent small-molecule inhibitors of anaplastic lymphoma kinase (ALK) containing a fused indoloquinoline scaffold. The most promising compound CJ-2360 has an IC 50 value of 2.2 nM against wild-type ALK and low-nanomolar potency against several clinically reported ALK mutants. This compound is capable of achieving complete tumor regression in the ALK-positive KARPAS-299 xenograft model with oral administration in mice. CJ-2360 represents a promising ALK inhibitor for advanced preclinical development.