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

Publication date: Available online 16 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Osamu Kurasawa, Yuya Oguro, Tohru Miyazaki, Misaki Homma, Kouji Mori, Kenichi Iwai, Hideto Hara, Robert Skene, Isaac Hoffman, Akihiro Ohashi, Sei Yoshida, Tomoyasu Ishikawa, Nobuo Cho
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.

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