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Diaminopyridine-based potent and selective mps1 kinase inhibitors binding to an unusual flipped-Peptide conformation.

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.

SUBMITTER: Kusakabe K

PROVIDER: S-EPMC4025729 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Diaminopyridine-based potent and selective mps1 kinase inhibitors binding to an unusual flipped-Peptide conformation.

Kusakabe Ken-Ichi K Ide Nobuyuki N Daigo Yataro Y Itoh Takeshi T Higashino Kenichi K Okano Yousuke Y Tadano Genta G Tachibana Yuki Y Sato Yuji Y Inoue Makiko M Wada Tooru T Iguchi Motofumi M Kanazawa Takayuki T Ishioka Yukichi Y Dohi Keiji K Tagashira Sachie S Kido Yasuto Y Sakamoto Shingo S Yasuo Kazuya K Maeda Masahiro M Yamamoto Takahiko T Higaki Masayo M Endoh Takeshi T Ueda Kazuo K Shiota Takeshi T Murai Hitoshi H Nakamura Yusuke Y

ACS medicinal chemistry letters 20120606 7

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. ...[more]

PMID: 24900510

Dataset Information

Diaminopyridine-based potent and selective mps1 kinase inhibitors binding to an unusual flipped-Peptide conformation.

Publications

Diaminopyridine-based potent and selective mps1 kinase inhibitors binding to an unusual flipped-Peptide conformation.

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