title: Discovery of novel furanone derivatives as potent Cdc7 kinase inhibitors.
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 IC50value 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.
authors.affiliation: 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.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Irie
authors.affiliation: Research and Development, Carna Biosciences, Inc., 3F BMA, 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan.
authors.forename: Tokiko
authors.initials: T
authors.lastname: Asami
authors.affiliation: Research and Development, Carna Biosciences, Inc., 3F BMA, 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Sawa
authors.affiliation: Research and Development, Carna Biosciences, Inc., 3F BMA, 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Uno
authors.affiliation: Research and Development, Carna Biosciences, Inc., 3F BMA, 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan.
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Hanada
authors.affiliation: Research and Development Department, SBI Biotech Co., Ltd., Izumi Garden Tower 18F, 1-6-1 Roppongi, Minato-ku, Tokyo 106-6018, Japan.
authors.forename: Chika
authors.initials: C
authors.lastname: Taniyama
authors.affiliation: Research and Development Department, SBI Biotech Co., Ltd., Izumi Garden Tower 18F, 1-6-1 Roppongi, Minato-ku, Tokyo 106-6018, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Funakoshi
authors.affiliation: Department of Genome Medicine, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Masai
authors.affiliation: Research and Development, Carna Biosciences, Inc., 3F BMA, 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Sawa
mesh_terms: D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D055808:Drug Discovery; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D018797:Cell Cycle Proteins; D005663:Furans; D047428:Protein Kinase Inhibitors; C068619:CDC7 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Anticancer activity; Apoptosis; Cell cycle; Furanone; Kinase inhibitors; Slow binding