8PY3

Crystal structure of human Sirt2 in complex with a 1,2,4-oxadiazole based inhibitor

Summary for 8PY3

• Entry DOI: 10.2210/pdb8py3/pdb
• Descriptor: NAD-dependent protein deacetylase sirtuin-2, ZINC ION, 4-chloranyl-~{N}-[4-[5-[[(3~{S})-1-[(3-fluoranyl-2-methyl-phenyl)methyl]piperidin-3-yl]methyl]-1,2,4-oxadiazol-3-yl]phenyl]benzamide, ... (6 entities in total)
• Functional Keywords: inhibitor, sirtuin 2, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 35520.73

Authors

Friedrich, F.,Colcerasa, A.,Einsle, O.,Jung, M. (deposition date: 2023-07-24, release date: 2024-06-19, Last modification date: 2024-07-10)

Primary citation

Colcerasa, A.,Friedrich, F.,Melesina, J.,Moser, P.,Vogelmann, A.,Tzortzoglou, P.,Neuwirt, E.,Sum, M.,Robaa, D.,Zhang, L.,Ramos-Morales, E.,Romier, C.,Einsle, O.,Metzger, E.,Schule, R.,Gross, O.,Sippl, W.,Jung, M.
Structure-Activity Studies of 1,2,4-Oxadiazoles for the Inhibition of the NAD + -Dependent Lysine Deacylase Sirtuin 2.
J.Med.Chem., 67:10076-10095, 2024

PubMed Abstract: The NAD-dependent lysine deacylase sirtuin 2 (Sirt2) is involved in multiple pathological conditions such as cancer. Targeting Sirt2 has thus received an increased interest for therapeutic purposes. Furthermore, the orthologue from (Sirt2) has been considered for the potential treatment of the neglected tropical disease schistosomiasis. We previously identified a 1,2,4-oxadiazole-based scaffold from the screening of the "Kinetobox" library as a dual inhibitor of human Sirt2 (hSirt2) and Sirt2. Herein, we describe the structure-activity studies on 1,2,4-oxadiazole-based analogues, which are potent inhibitors of human Sirt2 deacetylation. As proposed by docking studies, a substrate-competitive and cofactor-noncompetitive binding mode of inhibition could be determined binding assays and kinetic analysis and further confirmed by a crystal structure of an oxadiazole inhibitor in complex with hSirt2. Optimized analogues reduced cell viability and inhibited prostate cancer cell migration, in correlation with Sirt2 deacetylase inhibition both and in cells.

PubMed: 38847803
DOI: 10.1021/acs.jmedchem.4c00229

Experimental method

X-RAY DIFFRACTION (1.65 Å)