title: A unique hinge binder of extremely selective aminopyridine-based Mps1 (TTK) kinase inhibitors with cellular activity.
abstract: Mps1, also known as TTK, is a dual-specificity kinase that regulates the spindle assembly check point. Increased expression levels of Mps1 are observed in cancer cells, and the expression levels correlate well with tumor grade. Such evidence points to selective inhibition of Mps1 as an attractive strategy for cancer therapeutics. Starting from an aminopyridine-based lead 3a that binds to a flipped-peptide conformation at the hinge region in Mps1, elaboration of the aminopyridine scaffold at the 2- and 6-positions led to the discovery of 19c that exhibited no significant inhibition for 287 kinases as well as improved cellular Mps1 and antiproliferative activities in A549 lung carcinoma cells (cellular Mps1 IC₅₀=5.3 nM, A549 IC₅₀=26 nM). A clear correlation between cellular Mps1 and antiproliferative IC₅₀ values indicated that the antiproliferative activity observed in A549 cells would be responsible for the cellular inhibition of Mps1. The X-ray structure of 19c in complex with Mps1 revealed that this compound retains the ability to bind to the peptide flip conformation. Finally, comparative analysis of the X-ray structures of 19c, a deamino analogue 33, and a known Mps1 inhibitor bound to Mps1 provided insights into the unique binding mode at the hinge region.
authors: Medicinal Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan. Electronic address: ken-ichi.kusakabe@shionogi.co.jp.
authors: Ken-ichi
authors: K
authors: Kusakabe
authors: Medicinal Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors: Nobuyuki
authors: N
authors: Ide
authors: 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: Yataro
authors: Y
authors: Daigo
authors: Medicinal Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors: Takeshi
authors: T
authors: Itoh
authors: Innovative Drug Discovery Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors: Takahiko
authors: T
authors: Yamamoto
authors: Medicinal Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors: Eiichi
authors: E
authors: Kojima
authors: Medicinal Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors: Yasunori
authors: Y
authors: Mitsuoka
authors: Medicinal Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors: Genta
authors: G
authors: Tadano
authors: Medicinal Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors: Sachie
authors: S
authors: Tagashira
authors: Innovative Drug Discovery Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors: Kenichi
authors: K
authors: Higashino
authors: Innovative Drug Discovery Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors: Yousuke
authors: Y
authors: Okano
authors: Medicinal Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors: Yuji
authors: Y
authors: Sato
authors: Medicinal Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors: Makiko
authors: M
authors: Inoue
authors: Medicinal Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors: Motofumi
authors: M
authors: Iguchi
authors: Medicinal Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors: Takayuki
authors: T
authors: Kanazawa
authors: Medicinal Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors: Yukichi
authors: Y
authors: Ishioka
authors: Medicinal Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors: Keiji
authors: K
authors: Dohi
authors: Drug Developmental Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors: Yasuto
authors: Y
authors: Kido
authors: Drug Developmental Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors: Shingo
authors: S
authors: Sakamoto
authors: Medicinal Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors: Shigeru
authors: S
authors: Ando
authors: Innovative Drug Discovery Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors: Masahiro
authors: M
authors: Maeda
authors: Innovative Drug Discovery Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors: Masayo
authors: M
authors: Higaki
authors: Medicinal Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors: Hidenori
authors: H
authors: Yoshizawa
authors: Medicinal Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors: Hitoshi
authors: H
authors: Murai
authors: 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: Yusuke
authors: Y
authors: Nakamura
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D000631:Aminopyridines; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human
keywords: Cancer; Flipped peptide; Inhibitor; Kinase; Monopolar spindle 1; Mps1; Peptide flip; TTK