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

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

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English (US)
Pages (from-to)	438-448
Number of pages	11
Journal	European journal of medicinal chemistry
Volume	86
Issue number	1
DOIs	https://doi.org/10.1016/j.ejmech.2014.09.003
State	Published - Oct 30 2014
Externally published	Yes

Keywords

2,4-Diarylaminopyrimidine
2-Aminothiazole
ALK kinase
Gatekeeper mutation
Non-small-cell lung cancer

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

Access to Document

10.1016/j.ejmech.2014.09.003

Cite this

@article{f37d64ef3c6d40e796dfa4b2365cb6a8,

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

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",

author = "Zhiqing Liu and Xihua Yue and Zilan Song and Xia Peng and Junfeng Guo and Yinchun Ji and Zhen Cheng and Jian Ding and Jing Ai and Meiyu Geng and Ao Zhang",

year = "2014",

month = oct,

day = "30",

doi = "10.1016/j.ejmech.2014.09.003",

language = "English (US)",

volume = "86",

pages = "438--448",

journal = "European journal of medicinal chemistry",

issn = "0223-5234",

publisher = "Elsevier Masson SAS",

number = "1",

}

TY - JOUR

T1 - Design, synthesis and pharmacological evaluation of 2-(thiazol-2- amino)-4-arylaminopyrimidines as potent anaplastic lymphoma kinase (ALK) inhibitors

AU - Liu, Zhiqing

AU - Yue, Xihua

AU - Song, Zilan

AU - Peng, Xia

AU - Guo, Junfeng

AU - Ji, Yinchun

AU - Cheng, Zhen

AU - Ding, Jian

AU - Ai, Jing

AU - Geng, Meiyu

AU - Zhang, Ao

PY - 2014/10/30

Y1 - 2014/10/30

N2 - 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.

AB - 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.

KW - 2,4-Diarylaminopyrimidine

KW - 2-Aminothiazole

KW - ALK kinase

KW - Gatekeeper mutation

KW - Non-small-cell lung cancer

UR - http://www.scopus.com/inward/record.url?scp=84908043194&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84908043194&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2014.09.003

DO - 10.1016/j.ejmech.2014.09.003

M3 - Article

C2 - 25200979

AN - SCOPUS:84908043194

SN - 0223-5234

VL - 86

SP - 438

EP - 448

JO - European journal of medicinal chemistry

JF - European journal of medicinal chemistry

IS - 1

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this