Design, synthesis and pharmacological evaluation of 2-(thiazol-2-amino)-4-arylaminopyrimidines as potent anaplastic lymphoma kinase (ALK) inhibitors

• Published in: European journal of medicinal chemistry 2014-10, Vol.86, p.438-448
• Main Authors: Liu, Zhiqing, Yue, Xihua, Song, Zilan, Peng, Xia, Guo, Junfeng, Ji, Yinchun, Cheng, Zhen, Ding, Jian, Ai, Jing, Geng, Meiyu, Zhang, Ao
• Format: Article
• Language: English
• Subjects: 2,4-Diarylaminopyrimidine; 2-Aminothiazole; ALK kinase; Dose-Response Relationship, Drug; Drug Design; Gatekeeper mutation; Humans; Molecular Structure; Non-small-cell lung cancer; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - metabolism; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.09.003

A series of new 2,4-diarylaminopyrimidine analogues (DAAPalogues) was developed by incorporation of a substituted 2-aminothiazole component as the C-2 substituent of the center pyrimidine core. Compound 5i showed highest potency of 12.4 nM against ALK and 24.1 nM against ALK gatekeeper mutation L1196M. Although only having moderate cellular potency in the SUP-M2 cells harboring NPM-ALK, compound 5i showed good kinase selectivity and dose-dependently inhibited phosphorylation of ALK and its down-stream signaling pathways. [Display omitted] •ALK has been recognized as an emergent therapeutic target for cancer treatment.•New 2,4-diarylaminopyrimidines bearing an 2-aminothiazole motif was developed.•Compound 5i showed highest potency of 12.4 nM against ALK.•Compound 5i also showed 24.1 nM against ALK gatekeeper mutation L1196M.•5i dose-dependently inhibited phosphorylation of ALK and its down-stream pathways.