2017年4月
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
BIOORGANIC & MEDICINAL CHEMISTRY
- 巻
- 25
- 号
- 7
- 開始ページ
- 2133
- 終了ページ
- 2147
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1016/j.bmc.2017.02.021
- 出版者・発行元
- PERGAMON-ELSEVIER SCIENCE LTD
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. (C) 2017 Elsevier Ltd. All rights reserved.
- リンク情報
- ID情報
-
- DOI : 10.1016/j.bmc.2017.02.021
- ISSN : 0968-0896
- eISSN : 1464-3391
- PubMed ID : 28284870
- Web of Science ID : WOS:000398650800010