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

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• 作者：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
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：July 12, 2012
• 年：2012
• 卷：3
• 期：7
• 页码：560-564
• 全文大小：282K
• 年卷期：v.3,no.7(July 12, 2012)
• ISSN：1948-5875

文摘

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.

Keywords:

monopolar spindle 1; Mps 1; TTK; inhibitor; diaminopyridine; peptide flip; cancer