Discovery of a Dual SENP1 and SENP2 Inhibitor.

Autor: Brand M; Institute of Chemistry and Biotechnology, Competence Center for Drug Discovery, Zurich University of Applied Sciences (ZHAW), Einsiedlerstrasse 31, 8820 Wädenswil, Switzerland., Bommeli EB; Institute of Chemistry and Biotechnology, Competence Center for Drug Discovery, Zurich University of Applied Sciences (ZHAW), Einsiedlerstrasse 31, 8820 Wädenswil, Switzerland., Rütimann M; Institute of Chemistry and Biotechnology, Competence Center for Drug Discovery, Zurich University of Applied Sciences (ZHAW), Einsiedlerstrasse 31, 8820 Wädenswil, Switzerland., Lindenmann U; Institute of Chemistry and Biotechnology, Competence Center for Drug Discovery, Zurich University of Applied Sciences (ZHAW), Einsiedlerstrasse 31, 8820 Wädenswil, Switzerland., Riedl R; Institute of Chemistry and Biotechnology, Competence Center for Drug Discovery, Zurich University of Applied Sciences (ZHAW), Einsiedlerstrasse 31, 8820 Wädenswil, Switzerland.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2022 Oct 11; Vol. 23 (20). Date of Electronic Publication: 2022 Oct 11.
DOI: 10.3390/ijms232012085
Abstrakt: SUMOylation is a reversible post-translational modification (PTM) involving covalent attachment of small ubiquitin-related modifier (SUMO) proteins to substrate proteins. Dysregulation of SUMOylation and deSUMOylation results in cellular malfunction and is linked to various diseases, such as cancer. Sentrin-specific proteases (SENPs) were identified for the maturation of SUMOs and the deconjugation of SUMOs from their substrate proteins. Hence, this is a promising target tackling the dysregulation of the SUMOylation process. Herein, we report the discovery of a novel protein-protein interaction (PPI) inhibitor for SENP1-SUMO1 by virtual screening and subsequent medicinal chemistry optimization of the hit molecule. The optimized inhibitor ZHAWOC8697 showed IC 50 values of 8.6 μM against SENP1 and 2.3 μM against SENP2. With a photo affinity probe the SENP target was validated. This novel SENP inhibitor represents a new valuable tool for the study of SUMOylation processes and the SENP-associated development of small molecule-based treatment options.
Databáze: MEDLINE
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