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

  • ACS Med Chem Lett. 2012 Jun 6;3(7):560-4. doi: 10.1021/ml3000879.
Ken-Ichi Kusakabe  1 ,  Nobuyuki Ide  1 ,  Yataro Daigo  2 ,  Takeshi Itoh  1 ,  Kenichi Higashino  1 ,  Yousuke Okano  1 ,  Genta Tadano  1 ,  Yuki Tachibana  1 ,  Yuji Sato  1 ,  Makiko Inoue  1 ,  Tooru Wada  1 ,  Motofumi Iguchi  1 ,  Takayuki Kanazawa  1 ,  Yukichi Ishioka  1 ,  Keiji Dohi  1 ,  Sachie Tagashira  1 ,  Yasuto Kido  1 ,  Shingo Sakamoto  1 ,  Kazuya Yasuo  1 ,  Masahiro Maeda  1 ,  Takahiko Yamamoto  1 ,  Masayo Higaki  1 ,  Takeshi Endoh  1 ,  Kazuo Ueda  1 ,  Takeshi Shiota  1 ,  Hitoshi Murai  1 ,  Yusuke Nakamura  3
Affiliations
  • 1. Medicinal Research Laboratories, Drug Developmental Research Laboratories, and Innovative Drug Discovery Research Laboratories, Shionogi Pharmaceutical Research Center , 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
  • 2. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo , 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan ; Department of Medical Oncology, Shiga University of Medical Science , Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
  • 3. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo , 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
PMID: 24900510 DOI: 10.1021/ml3000879
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.

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