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

Zhiqing Liu; Xihua Yue; Zilan Song; Xia Peng; Junfeng Guo; Yinchun Ji; Zhen Cheng; Jian Ding; Jing Ai; Meiyu Geng; Ao Zhang

doi:10.1016/j.ejmech.2014.09.003

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

Eur J Med Chem. 2014 Oct 30:86:438-48. doi: 10.1016/j.ejmech.2014.09.003. Epub 2014 Sep 4.

Authors

Zhiqing Liu¹, Xihua Yue², Zilan Song¹, Xia Peng², Junfeng Guo¹, Yinchun Ji², Zhen Cheng³, Jian Ding², Jing Ai², Meiyu Geng⁴, Ao Zhang⁵

Affiliations

¹ CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica (SIMM), Shanghai 201203, China.
² Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Shanghai 201203, China.
³ Molecular Imaging Program at Stanford, Bio-X Program, Department of Radiology, School of Medicine, Stanford University, Stanford, CA 94305-5484, USA.
⁴ Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Shanghai 201203, China. Electronic address: [email protected].
⁵ CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica (SIMM), Shanghai 201203, China. Electronic address: [email protected].

PMID: 25200979
DOI: 10.1016/j.ejmech.2014.09.003

Abstract

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.

Keywords: 2,4-Diarylaminopyrimidine; 2-Aminothiazole; ALK kinase; Gatekeeper mutation; Non-small-cell lung cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anaplastic Lymphoma Kinase
Dose-Response Relationship, Drug
Drug Design*
Humans
Molecular Structure
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*

Substances

Protein Kinase Inhibitors
Pyrimidines
Thiazoles
ALK protein, human
Anaplastic Lymphoma Kinase
Receptor Protein-Tyrosine Kinases