6F5H

Crystal structure of USP7 in complex with a 4-hydroxypiperidine based inhibitor

Summary for 6F5H

• Entry DOI: 10.2210/pdb6f5h/pdb
• Related: 5N9R 5N9T
• Descriptor: Ubiquitin carboxyl-terminal hydrolase 7, SULFATE ION, GLYCEROL, ... (5 entities in total)
• Functional Keywords: usp7, reversible, inhibitor, selective, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : Q93009
• Total number of polymer chains: 2
• Total formula weight: 84327.20

Authors

Harrison, T.,Gavory, G.,O'Dowd, C.,Helm, M.,Flasz, J.,Dossang, A.,Hughes, C.,Cassidy, E.,McClelland, K.,Odrzywol, E.,Page, N.,Barker, O.,Miel, H.,Feutron-Burton, S.,Rountree, J.S.S. (deposition date: 2017-12-01, release date: 2018-04-11, Last modification date: 2024-05-08)

Primary citation

O'Dowd, C.R.,Helm, M.D.,Rountree, J.S.S.,Flasz, J.T.,Arkoudis, E.,Miel, H.,Hewitt, P.R.,Jordan, L.,Barker, O.,Hughes, C.,Rozycka, E.,Cassidy, E.,McClelland, K.,Odrzywol, E.,Page, N.,Feutren-Burton, S.,Dvorkin, S.,Gavory, G.,Harrison, T.
Identification and Structure-Guided Development of Pyrimidinone Based USP7 Inhibitors.
ACS Med Chem Lett, 9:238-243, 2018

PubMed Abstract: Ubiquitin specific protease 7 (USP7, HAUSP) has become an attractive target in drug discovery due to the role it plays in modulating Mdm2 levels and consequently p53. Increasing interest in USP7 is emerging due to its potential involvement in oncogenic pathways as well as possible roles in both metabolic and immune disorders in addition to viral infections. Potent, novel, and selective inhibitors of USP7 have been developed using both rational and structure-guided design enabled by high-resolution cocrystallography. Initial hits were identified via fragment-based screening, scaffold-hopping, and hybridization exercises. Two distinct subseries are described along with associated structure-activity relationship trends, as are initial efforts aimed at developing compounds suitable for experiments. Overall, these discoveries will enable further research into the wider biological role of USP7.

PubMed: 29541367
DOI: 10.1021/acsmedchemlett.7b00512

Experimental method

X-RAY DIFFRACTION (2.16 Å)