Gutenberg Open Science: Subnanomolar cathepsin S inhibitors with high selectivity : optimizing covalent reversible α-fluorovinylsulfones and α-sulfonates as potential immunomodulators cancer

Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-9524

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DC Field	Value	Language
dc.contributor.author	Fuchs, Natalie	-
dc.contributor.author	Meta, Mergim	-
dc.contributor.author	Lantzberg, Bellinda	-
dc.contributor.author	Bros, Matthias	-
dc.contributor.author	Kuan, Seah Ling	-
dc.contributor.author	Weil, Tanja	-
dc.contributor.author	Schirmeister, Tanja	-
dc.date.accessioned	2023-09-12T08:31:39Z	-
dc.date.available	2023-09-12T08:31:39Z	-
dc.date.issued	2023	-
dc.identifier.uri	https://openscience.ub.uni-mainz.de/handle/20.500.12030/9542	-
dc.description.abstract	The cysteine protease cathepsin S (CatS) is overexpressed in many tumors. It is known to be involved in tumor progression as well as antigen processing in antigen-presenting cells (APC). Recent evidence suggests that silencing CatS improves the anti-tumor immune response in several cancers. Therefore, CatS is an interesting target to modulate the immune response in these diseases. Here, we present a series of covalent-reversible CatS inhibitors based on the α-fluorovinylsulfone and -sulfonate warheads. We optimized two lead structures by molecular docking approaches, resulting in 22 final compounds which were evaluated in fluorometric enzyme assays for CatS inhibition and for selectivity towards the off-targets CatB and CatL. The most potent inhibitor in the series has subnanomolar affinity (Ki=0.08 nM) and more than 100,000-fold selectivity towards cathepsins B and L. These new reversible and non-cytotoxic inhibitors could serve as interesting leads to develop new immunomodulators in cancer therapy.	en_GB
dc.description.sponsorship	Deutsche Forschungsgemeinschaft (DFG)\|491381577\|Open-Access-Publikationskosten 2022–2024 Universität Mainz - Universitätsmedizin	-
dc.language.iso	eng	de
dc.rights	CC BY	*
dc.rights.uri	https://creativecommons.org/licenses/by/4.0/	*
dc.subject.ddc	540 Chemie	de_DE
dc.subject.ddc	540 Chemistry and allied sciences	en_GB
dc.subject.ddc	610 Medizin	de_DE
dc.subject.ddc	610 Medical sciences	en_GB
dc.title	Subnanomolar cathepsin S inhibitors with high selectivity : optimizing covalent reversible α-fluorovinylsulfones and α-sulfonates as potential immunomodulators cancer	en_GB
dc.type	Zeitschriftenaufsatz	de
dc.identifier.doi	http://doi.org/10.25358/openscience-9524	-
jgu.type.dinitype	article	en_GB
jgu.type.version	Published version	de
jgu.type.resource	Text	de
jgu.organisation.department	FB 04 Medizin	de
jgu.organisation.department	FB 09 Chemie, Pharmazie u. Geowissensch.	de
jgu.organisation.number	2700	-
jgu.organisation.number	7950	-
jgu.organisation.name	Johannes Gutenberg-Universität Mainz	-
jgu.rights.accessrights	openAccess	-
jgu.journal.title	ChemMedChem	de
jgu.journal.volume	18	de
jgu.journal.issue	15	de
jgu.pages.alternative	e202300160	de
jgu.publisher.year	2023	-
jgu.publisher.name	Wiley-VCH	de
jgu.publisher.place	Weinheim	de
jgu.publisher.issn	1860-7187	de
jgu.organisation.place	Mainz	-
jgu.subject.ddccode	540	de
jgu.subject.ddccode	610	de
jgu.publisher.doi	10.1002/cmdc.202300160	de
jgu.organisation.ror	https://ror.org/023b0x485	-
Appears in collections:	DFG-491381577-H

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