• Ken-ichi Kusakabe, Nobuyuki Ide, Yataro Daigo, Takeshi Itoh, Takahiko Yamamoto, Eiichi Kojima, Yasunori Mitsuoka, Genta Tadano, Sachie Tagashira, Kenichi Higashino, Yousuke Okano, Yuji Sato, Makiko Inoue, Motofumi Iguchi, Takayuki Kanazawa, Yukichi Ishioka, Keiji Dohi, Yasuto Kido, Shingo Sakamoto, Shigeru Ando, Masahiro Maeda, Masayo Higaki, Hidenori Yoshizawa, Hitoshi Murai, and Yusuke Nakamura.
• 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.
• Bioorg. Med. Chem. 2015 May 1; 23 (9): 2247-60.

AbstractMps1, 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.Copyright © 2015 Elsevier Ltd. All rights reserved.

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