Structure-Activity Studies of 1,2,4-Oxadiazoles for the Inhibition of the NAD + -Dependent Lysine Deacylase Sirtuin 2.

Autor: Colcerasa A; Institute of Pharmaceutical Sciences, University of Freiburg, Albertstraße 25, Freiburg 79104, Germany., Friedrich F; Institute of Pharmaceutical Sciences, University of Freiburg, Albertstraße 25, Freiburg 79104, Germany., Melesina J; Department of Medicinal Chemistry, Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, Wolfgang-Langenbeck-Straße 4, Halle/Saale 06120, Germany., Moser P; Institute of Pharmaceutical Sciences, University of Freiburg, Albertstraße 25, Freiburg 79104, Germany., Vogelmann A; Institute of Pharmaceutical Sciences, University of Freiburg, Albertstraße 25, Freiburg 79104, Germany.; CIBSS─Centre for Integrative Biological Signalling Studies, Freiburg 79104, Germany., Tzortzoglou P; Institute of Pharmaceutical Sciences, University of Freiburg, Albertstraße 25, Freiburg 79104, Germany., Neuwirt E; Institute of Neuropathology, University of Freiburg Medical Center, Breisacher Straße 113, Freiburg 79106, Germany., Sum M; Department of Urology and Center for Clinical Research, University of Freiburg Medical Center, Breisacher Straße 66, Freiburg 79106, Germany., Robaa D; Department of Medicinal Chemistry, Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, Wolfgang-Langenbeck-Straße 4, Halle/Saale 06120, Germany., Zhang L; Institute of Biochemistry, University of Freiburg, Albertstraße 21, Freiburg 79104, Germany., Ramos-Morales E; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, CNRS UMR 7104, Inserm UMR-S 1258, 1 Rue Laurent Fries, Illkirch F-67400, France., Romier C; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, CNRS UMR 7104, Inserm UMR-S 1258, 1 Rue Laurent Fries, Illkirch F-67400, France., Einsle O; Institute of Biochemistry, University of Freiburg, Albertstraße 21, Freiburg 79104, Germany., Metzger E; Department of Urology and Center for Clinical Research, University of Freiburg Medical Center, Breisacher Straße 66, Freiburg 79106, Germany., Schüle R; Department of Urology and Center for Clinical Research, University of Freiburg Medical Center, Breisacher Straße 66, Freiburg 79106, Germany.; CIBSS─Centre for Integrative Biological Signalling Studies, Freiburg 79104, Germany., Groß O; Institute of Neuropathology, University of Freiburg Medical Center, Breisacher Straße 113, Freiburg 79106, Germany., Sippl W; Department of Medicinal Chemistry, Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, Wolfgang-Langenbeck-Straße 4, Halle/Saale 06120, Germany., Jung M; Institute of Pharmaceutical Sciences, University of Freiburg, Albertstraße 25, Freiburg 79104, Germany.; CIBSS─Centre for Integrative Biological Signalling Studies, Freiburg 79104, Germany.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2024 Jun 27; Vol. 67 (12), pp. 10076-10095. Date of Electronic Publication: 2024 Jun 07.
DOI: 10.1021/acs.jmedchem.4c00229
Abstrakt: 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 Schistosoma mansoni ( Sm 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 Sm 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 in vitro via 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 in vitro and in cells.
Databáze: MEDLINE
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