5U7Q

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

5U7Q の概要

• エントリーDOI: 10.2210/pdb5u7q/pdb
• 関連するPDBエントリー: 5U7R
• 分子名称: Rho-associated protein kinase 2 (2 entities in total)
• 機能のキーワード: serine/threonine kinase, apo-protein, transferase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: O75116
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 181602.58

構造登録者

Hoffman, I.D. (登録日: 2016-12-12, 公開日: 2017-03-29, 最終更新日: 2024-03-06)

主引用文献

Kurasawa, O.,Oguro, Y.,Miyazaki, T.,Homma, M.,Mori, K.,Iwai, K.,Hara, H.,Skene, R.,Hoffman, I.,Ohashi, A.,Yoshida, S.,Ishikawa, T.,Cho, N.
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.
Bioorg. Med. Chem., 25:2133-2147, 2017

PubMed 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.

PubMed: 28284870
DOI: 10.1016/j.bmc.2017.02.021

実験手法

X-RAY DIFFRACTION (3.15 Å)