title: Identification of a new class of potent Cdc7 inhibitors designed by putative pharmacophore model: Synthesis and biological evaluation of 2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-ones.
abstract: Cell division cycle 7 (Cdc7) is a serine/threonine kinase that plays important roles in the regulation of DNA replication process. A genetic study indicates that Cdc7 inhibition can induce selective tumor-cell death in a p53-dependent manner, suggesting that Cdc7 is an attractive target for the treatment of cancers. In order to identify a new class of potent Cdc7 inhibitors, we generated a putative pharmacophore model based on in silico docking analysis of a known inhibitor with Cdc7 homology model. The pharmacophore model provided a minimum structural motif of Cdc7 inhibitor, by which preliminary medicinal chemistry efforts identified a dihydrothieno[3,2-d]-pyrimidin-4(1H)-one scaffold having a heteroaromatic hinge-binding moiety. The structure-activity relationship (SAR) studies resulted in the discovery of new, potent, and selective Cdc7 inhibitors 14a, c, e. Furthermore, the high selectivity of 14c, e for Cdc7 over Rho-associated protein kinase 1 (ROCK1) is discussed by utilizing a docking study with Cdc7 and ROCK2 crystal structures.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: osamu.kurasawa@takeda.com.
authors.forename: Osamu
authors.initials: O
authors.lastname: Kurasawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Oguro
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Miyazaki
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Misaki
authors.initials: M
authors.lastname: Homma
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Kouji
authors.initials: K
authors.lastname: Mori
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Iwai
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hideto
authors.initials: H
authors.lastname: Hara
authors.affiliation: Takeda California, Inc., 10410 Science Center Drive, San Diego 92121, CA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Skene
authors.affiliation: Takeda California, Inc., 10410 Science Center Drive, San Diego 92121, CA, USA.
authors.forename: Isaac
authors.initials: I
authors.lastname: Hoffman
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ohashi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Sei
authors.initials: S
authors.lastname: Yoshida
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Cho
mesh_terms: D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D018797:Cell Cycle Proteins; D011744:Pyrimidinones; C068619:CDC7 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Cell division cycle 7 (Cdc7); Dihydrothieno[3,2-d]-pyrimidin-4(1H)-one; Pharmacophore model