Discovery of novel furanone derivatives as potent Cdc7 kinase inhibitors

Takayuki Irie; Tokiko Asami; Ayako Sawa; Yuko Uno; Mitsuharu Hanada; Chika Taniyama; Yoko Funakoshi; Hisao Masai; Masaaki Sawa

doi:10.1016/j.ejmech.2017.02.030

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. Epub 2017 Feb 17.

Authors

Takayuki Irie¹, Tokiko Asami², Ayako Sawa², Yuko Uno², Mitsuharu Hanada², Chika Taniyama³, Yoko Funakoshi³, Hisao Masai⁴, Masaaki Sawa²

Affiliations

¹ Research and Development, Carna Biosciences, Inc., 3F BMA, 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan. Electronic address: takayuki.irie@carnabio.com.
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.

MeSH terms

Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / drug effects
Cell Death / drug effects
Cell Line, Tumor
Drug Discovery
Furans / pharmacology*
Humans
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Cell Cycle Proteins
Furans
Protein Kinase Inhibitors
CDC7 protein, human
Protein Serine-Threonine Kinases