Discovery of novel furanone derivatives as potent Cdc7 kinase inhibitors

  • Eur J Med Chem. 2017 Apr 21;130:406-418. doi: 10.1016/j.ejmech.2017.02.030.
Takayuki Irie  1 ,  Tokiko Asami  2 ,  Ayako Sawa  2 ,  Yuko Uno  2 ,  Mitsuharu Hanada  2 ,  Chika Taniyama  3 ,  Yoko Funakoshi  3 ,  Hisao Masai  4 ,  Masaaki Sawa  2
Affiliations
  • 1. Research and Development, Carna Biosciences, Inc., 3F BMA, 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan. Electronic address: [email protected].
  • 2. Research and Development, Carna Biosciences, Inc., 3F BMA, 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan.
  • 3. Research and Development Department, SBI Biotech Co., Ltd., Izumi Garden Tower 18F, 1-6-1 Roppongi, Minato-ku, Tokyo 106-6018, Japan.
  • 4. Department of Genome Medicine, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
PMID: 28279847 DOI: 10.1016/j.ejmech.2017.02.030
Abstract

Cdc7 is a serine-threonine kinase and plays a conserved and important role in DNA replication, and it has been recognized as a potential Anticancer target. Herein, we report the design, synthesis and structure-activity relationship of novel furanone derivatives as Cdc7 kinase inhibitors. Compound 13 was identified as a strong inhibitor of Cdc7 with an IC50 value of 0.6 nM in the presence of 1 mM ATP and showed excellent kinase selectivity. In addition, it exhibited slow off-rate characteristics, which may offer advantages over known Cdc7 inhibitors in its potential to yield prolonged inhibitory effects in vivo. Compound 13 potently inhibited Cdc7 activity in Cancer cells, and effectively induced cell death.

Keywords
Anticancer activity; Apoptosis; Cell cycle; Furanone; Kinase inhibitors; Slow binding.
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