6VN2

USP7 IN COMPLEX WITH LIGAND COMPOUND 18

6VN2 の概要

• エントリーDOI: 10.2210/pdb6vn2/pdb
• 分子名称: Ubiquitin carboxyl-terminal hydrolase 7, 1-({7-[(2R)-5-chloro-2-(piperazine-1-carbonyl)-2,3-dihydro-1-benzofuran-7-yl]thieno[3,2-b]pyridin-2-yl}methyl)-1H-pyrrole-2,5-dione, ACETATE ION, ... (4 entities in total)
• 機能のキーワード: usp7, dub, deubiquitinase, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 82032.51

構造登録者

Leger, P.R.,Wustrow, D.J.,Hu, D.X.,Krapp, S.,Maskos, K.,Blaesse, M. (登録日: 2020-01-29, 公開日: 2020-04-29, 最終更新日: 2024-11-13)

主引用文献

Leger, P.R.,Hu, D.X.,Biannic, B.,Bui, M.,Han, X.,Karbarz, E.,Maung, J.,Okano, A.,Osipov, M.,Shibuya, G.M.,Young, K.,Higgs, C.,Abraham, B.,Bradford, D.,Cho, C.,Colas, C.,Jacobson, S.,Ohol, Y.M.,Pookot, D.,Rana, P.,Sanchez, J.,Shah, N.,Sun, M.,Wong, S.,Brockstedt, D.G.,Kassner, P.D.,Schwarz, J.B.,Wustrow, D.J.
Discovery of Potent, Selective, and Orally Bioavailable Inhibitors of USP7 with In Vivo Antitumor Activity.
J.Med.Chem., 63:5398-5420, 2020

PubMed Abstract: USP7 is a promising target for cancer therapy as its inhibition is expected to decrease function of oncogenes, increase tumor suppressor function, and enhance immune function. Using a structure-based drug design strategy, a new class of reversible USP7 inhibitors has been identified that is highly potent in biochemical and cellular assays and extremely selective for USP7 over other deubiquitinases. The succinimide was identified as a key potency-driving motif, forming two strong hydrogen bonds to the allosteric pocket of USP7. Redesign of an initial benzofuran-amide scaffold yielded a simplified ether series of inhibitors, utilizing acyclic conformational control to achieve proper amine placement. Further improvements were realized upon replacing the ether-linked amines with carbon-linked morpholines, a modification motivated by free energy perturbation (FEP+) calculations. This led to the discovery of compound , a highly potent, selective, and orally bioavailable USP7 inhibitor. In xenograft studies, compound demonstrated tumor growth inhibition in both p53 wildtype and p53 mutant cancer cell lines, demonstrating that USP7 inhibitors can suppress tumor growth through multiple different pathways.

PubMed: 32302140
DOI: 10.1021/acs.jmedchem.0c00245

実験手法

X-RAY DIFFRACTION (2.93 Å)