Discovery of CJ-2360 as a Potent and Orally Active Inhibitor of Anaplastic Lymphoma Kinase Capable of Achieving Complete Tumor Regression

• Published in: Journal of medicinal chemistry Vol. 63; no. 22; pp. 13994 - 14016
• Main Authors: Chen, Jianyong, Zhou, Yunlong, Dong, Xuyuan, Liu, Liu, Bai, Longchuan, McEachern, Donna, Przybranowski, Sally, Yang, Chao-Yie, Stuckey, Jeanne, Li, Xiaoqin, Wen, Bo, Zhao, Ting, Sun, Siwei, Sun, Duxin, Jiao, Lingling, Jing, Yu, Guo, Ming, Yang, Dajun, Wang, Shaomeng
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.11.2020; Amer Chemical Soc
• Subjects: Administration, Oral; Anaplastic Lymphoma Kinase - antagonists & inhibitors; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Cell Proliferation; Chemistry, Medicinal; Disease Progression; Drug Discovery; Female; Humans; Life Sciences & Biomedicine; Lymphoma, Large-Cell, Anaplastic - drug therapy; Lymphoma, Large-Cell, Anaplastic - enzymology; Lymphoma, Large-Cell, Anaplastic - pathology; Mice; Mice, SCID; Pharmacology & Pharmacy; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Science & Technology; Structure-Activity Relationship; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01550

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 IC50 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.