2. Academic Validation
  3. Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity

Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity

  • J Med Chem. 2015 Feb 26;58(4):1760-75. doi: 10.1021/jm501599u.
Ken-Ichi Kusakabe 1,  Nobuyuki Ide,  Yataro Daigo,  Takeshi Itoh,  Takahiko Yamamoto,  Hiroshi Hashizume,  Kohei Nozu,  Hiroshi Yoshida,  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,  Yoshiyasu Baba,  Yusuke Nakamura
Affiliations

Affiliation

  • 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.
PMID: 25625617 DOI: 10.1021/jm501599u
Abstract

Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in Cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 Inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue Cancer cell lines.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12658
    Mps1 Inhibitor