Identification of potent and selective MTH1 inhibitors

被引：61

作者：

Petrocchi, Alessia ^{[1
]}

Leo, Elisabetta ^{[1
,2
]}

Reyna, Naphtali J. ^{[1
]}

Hamilton, Matthew M. ^{[1
]}

Shi, Xi ^{[1
]}

Parker, Connor A. ^{[1
]}

Mseeh, Faika ^{[1
]}

Bardenhagen, Jennifer P. ^{[1
]}

Leonard, Paul ^{[1
]}

Cross, Jason B. ^{[1
]}

Huang, Sha ^{[1
]}

Jiang, Yongying ^{[1
]}

Cardozo, Mario ^{[1
,3
]}

Draetta, Giulio ^{[1
]}

Marszalek, Joseph R. ^{[1
]}

Toniatti, Carlo ^{[1
]}

Jones, Philip ^{[1
]}

Lewis, Richard T. ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, 1901 East Rd, Houston, TX 77054 USA

[2] Canc Res Technol Discovery Labs, Jonas Webb Bldg,Babraham Res Campus, Cambridge CB22 3AT, England

[3] Nurix, 1700 Owens St Suite 290, San Francisco, CA 94158 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 06期

关键词：

MTH1; inhibitors; Antitumor; IACS-4759; 2-Aminopyrimidine; CANCER; DOCKING; GLIDE; POOL; DNA;

D O I：

10.1016/j.bmcl.2016.02.026

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Structure based design of a novel class of aminopyrimidine MTH1 (MutT homolog 1) inhibitors is described. Optimization led to identification of IACS-4759 (compound 5), a sub-nanomolar inhibitor of MTH1 with excellent cell permeability and good metabolic stability in microsomes. This compound robustly inhibited MTH1 activity in cells and proved to be an excellent tool for interrogation of the utility of MTH1 inhibition in the context of oncology. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：1503 / 1507

页数：5

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