Diaminopyridine-based Potent and Selective Mps1 Kinase Inhibitors Binding to an Unusual Flipped-Peptide Conformation

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2014 Jun 6

PMID 24900510

Citations 10

Authors

Ken-Ichi Kusakabe

Nobuyuki Ide

Yataro Daigo

Takeshi Itoh

Kenichi Higashino

Yousuke Okano

Genta Tadano

Yuki Tachibana

Yuji Sato

Makiko Inoue

Tooru Wada

Motofumi Iguchi

Takayuki Kanazawa

Yukichi Ishioka

Keiji Dohi

Sachie Tagashira

Yasuto Kido

Shingo Sakamoto

Kazuya Yasuo

Masahiro Maeda

Takahiko Yamamoto

Masayo Higaki

Takeshi Endoh

Kazuo Ueda

Takeshi Shiota

Hitoshi Murai

Yusuke Nakamura

Affiliations

Soon will be listed here.

Abstract

Monopolar spindle 1 (Mps1) is an attractive cancer drug target due to the important role that it plays in centrosome duplication, the spindle assembly checkpoint, and the maintenance of chromosomal stability. A design based on JNK inhibitors with an aminopyridine scaffold and subsequent modifications identified diaminopyridine 9 with an IC50 of 37 nM. The X-ray structure of 9 revealed that the Cys604 carbonyl group of the hinge region flips to form a hydrogen bond with the aniline NH group in 9. Further optimization of 9 led to 12 with improved cellular activity, suitable pharmacokinetic profiles, and good in vivo efficacy in the mouse A549 xenograft model. Moreover, 12 displayed excellent selectivity over 95 kinases, indicating the contribution of its unusual flipped-peptide conformation to its selectivity.

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