Novel 2,4-Diarylaminopyrimidine Analogues (DAAPalogues) Showing Potent c-Met/ALK Multikinase Inhibitory Activities

Zhiqing Liu; Jing Ai; Xia Peng; Zilan Song; Kui Wu; Jing Zhang; Qizheng Yao; Yi Chen; Yinchun Ji; Yanhong Yang; Meiyu Geng; Ao Zhang

doi:10.1021/ml400373j

Novel 2,4-Diarylaminopyrimidine Analogues (DAAPalogues) Showing Potent c-Met/ALK Multikinase Inhibitory Activities

ACS Med Chem Lett. 2014 Feb 8;5(4):304-8. doi: 10.1021/ml400373j. eCollection 2014 Apr 10.

Authors

Zhiqing Liu¹, Jing Ai¹, Xia Peng¹, Zilan Song¹, Kui Wu², Jing Zhang¹, Qizheng Yao², Yi Chen¹, Yinchun Ji¹, Yanhong Yang¹, Meiyu Geng¹, Ao Zhang¹

Affiliations

¹ CAS Key Laboratory of Receptor Research, and Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences , Shanghai 201203, China.
² Department of Medicinal Chemistry, China Pharmaceutical University , Nanjing 210009, China.

Abstract

By repurposing a typical dopamine D1/D5 receptor agonist motif, C1-substituted-N3-benzazepine or benzazecine, into the classical RTK inhibitor 2,4-diaminopyrimidine skeleton, a series of new 2,4-diarylaminopyrimidine analogues (DAAPalogues) were developed. Compounds 7 and 8a were identified possessing high potency against both c-Met and ALK kinases. Compound 8a displayed appreciable antitumor efficacy at the dose of 1 mg/kg in the ALK-driven BF3/EML4-ALK xenograft mice model.

Keywords: 2,4-diarylaminopyrimidine analogues; C1-Substituted-N3-benzazepine; c-Met/ALK dual inhibitor; structure repurposing.