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

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

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 re...

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Veröffentlicht in:Journal of medicinal chemistry 2020-11, Vol.63 (22), p.13994-14016
Hauptverfasser: 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: Artikel
Sprache:eng
Schlagworte:
Administration, Oral
Anaplastic Lymphoma Kinase - antagonists & inhibitors
Animals
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Apoptosis
Cell Proliferation
Disease Progression
Drug Discovery
Female
Humans
Lymphoma, Large-Cell, Anaplastic - drug therapy
Lymphoma, Large-Cell, Anaplastic - enzymology
Lymphoma, Large-Cell, Anaplastic - pathology
Mice
Mice, SCID
Protein Kinase Inhibitors - administration & dosage
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Structure-Activity Relationship
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
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Zusammenfassung: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.0c01550