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

  • J Med Chem. 2020 Nov 25;63(22):13994-14016. doi: 10.1021/acs.jmedchem.0c01550.
Jianyong Chen  1  2 ,  Yunlong Zhou  2 ,  Xuyuan Dong  1 ,  Liu Liu  1 ,  Longchuan Bai  1 ,  Donna McEachern  1 ,  Sally Przybranowski  1 ,  Chao-Yie Yang  1 ,  Jeanne Stuckey  3 ,  Xiaoqin Li  4 ,  Bo Wen  4 ,  Ting Zhao  4 ,  Siwei Sun  4 ,  Duxin Sun  4 ,  Lingling Jiao  2 ,  Yu Jing  2 ,  Ming Guo  2 ,  Dajun Yang  2 ,  Shaomeng Wang  1
Affiliations
  • 1. Rogel Cancer Center and Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 2. Ascentage Pharma (Jiangsu), Medical City Avenue, QB3 Building First Floor, Taizhou, Jiangsu Province 225300, China.
  • 3. Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 4. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 33185101 DOI: 10.1021/acs.jmedchem.0c01550
Abstract

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.

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