title: 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.
authors.affiliation: 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.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Kusakabe
authors.affiliation: 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.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Ide
authors.affiliation: 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.
authors.forename: Yataro
authors.initials: Y
authors.lastname: Daigo
authors.affiliation: 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.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Itoh
authors.affiliation: 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.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Higashino
authors.affiliation: 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.
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Okano
authors.affiliation: 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.
authors.forename: Genta
authors.initials: G
authors.lastname: Tadano
authors.affiliation: 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.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tachibana
authors.affiliation: 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.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sato
authors.affiliation: 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.
authors.forename: Makiko
authors.initials: M
authors.lastname: Inoue
authors.affiliation: 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.
authors.forename: Tooru
authors.initials: T
authors.lastname: Wada
authors.affiliation: 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.
authors.forename: Motofumi
authors.initials: M
authors.lastname: Iguchi
authors.affiliation: 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.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kanazawa
authors.affiliation: 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.
authors.forename: Yukichi
authors.initials: Y
authors.lastname: Ishioka
authors.affiliation: 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.
authors.forename: Keiji
authors.initials: K
authors.lastname: Dohi
authors.affiliation: 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.
authors.forename: Sachie
authors.initials: S
authors.lastname: Tagashira
authors.affiliation: 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.
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Kido
authors.affiliation: 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.
authors.forename: Shingo
authors.initials: S
authors.lastname: Sakamoto
authors.affiliation: 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.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Yasuo
authors.affiliation: 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.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Maeda
authors.affiliation: 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.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: 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.
authors.forename: Masayo
authors.initials: M
authors.lastname: Higaki
authors.affiliation: 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.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Endoh
authors.affiliation: 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.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ueda
authors.affiliation: 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.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shiota
authors.affiliation: 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.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Murai
authors.affiliation: 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.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
keywords: Mps 1; TTK; cancer; diaminopyridine; inhibitor; monopolar spindle 1; peptide flip