Discovery of a dual SENP1 and SENP2 inhibitor

Brand, Michael; Bommeli, Elias Benjamin; Rütimann, Marc; Lindenmann, Urs; Riedl, Rainer

doi:10.3390/ijms232012085

Please use this identifier to cite or link to this item: https://doi.org/10.21256/zhaw-26647

Publication type:	Article in scientific journal
Type of review:	Peer review (publication)
Title:	Discovery of a dual SENP1 and SENP2 inhibitor
Authors:	Brand, Michael Bommeli, Elias Benjamin Rütimann, Marc Lindenmann, Urs Riedl, Rainer
et. al:	No
DOI:	10.3390/ijms232012085 10.21256/zhaw-26647
Published in:	International Journal of Molecular Sciences
Volume(Issue):	23
Issue:	20
Page(s):	12085
Issue Date:	11-Oct-2022
Publisher / Ed. Institution:	MDPI
ISSN:	1422-0067
Language:	English
Subjects:	SENP; Cancer; Deubiquitinating enzyme; Drug discovery; Inhibitor; Medicinal chemistry; Small molecule; Structure activity relationship; Pyruvate; Endopeptidases; Peptide hydrolase; Small ubiquitin-related modifier protein; Sumoylation
Subject (DDC):	572: Biochemistry
Abstract:	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 IC50 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.
URI:	https://digitalcollection.zhaw.ch/handle/11475/26647
Fulltext version:	Published version
License (according to publishing contract):	CC BY 4.0: Attribution 4.0 International
Departement:	Life Sciences and Facility Management
Organisational Unit:	Institute of Chemistry and Biotechnology (ICBT)
Appears in collections:	Publikationen Life Sciences und Facility Management

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Brand, M., Bommeli, E. B., Rütimann, M., Lindenmann, U., & Riedl, R. (2022). Discovery of a dual SENP1 and SENP2 inhibitor. International Journal of Molecular Sciences, 23(20), 12085. https://doi.org/10.3390/ijms232012085

Brand, M. et al. (2022) ‘Discovery of a dual SENP1 and SENP2 inhibitor’, International Journal of Molecular Sciences, 23(20), p. 12085. Available at: https://doi.org/10.3390/ijms232012085.

M. Brand, E. B. Bommeli, M. Rütimann, U. Lindenmann, and R. Riedl, “Discovery of a dual SENP1 and SENP2 inhibitor,” International Journal of Molecular Sciences, vol. 23, no. 20, p. 12085, Oct. 2022, doi: 10.3390/ijms232012085.

BRAND, Michael, Elias Benjamin BOMMELI, Marc RÜTIMANN, Urs LINDENMANN und Rainer RIEDL, 2022. Discovery of a dual SENP1 and SENP2 inhibitor. International Journal of Molecular Sciences. 11 Oktober 2022. Bd. 23, Nr. 20, S. 12085. DOI 10.3390/ijms232012085

Brand, Michael, Elias Benjamin Bommeli, Marc Rütimann, Urs Lindenmann, and Rainer Riedl. 2022. “Discovery of a Dual SENP1 and SENP2 Inhibitor.” International Journal of Molecular Sciences 23 (20): 12085. https://doi.org/10.3390/ijms232012085.

Brand, Michael, et al. “Discovery of a Dual SENP1 and SENP2 Inhibitor.” International Journal of Molecular Sciences, vol. 23, no. 20, Oct. 2022, p. 12085, https://doi.org/10.3390/ijms232012085.