Autoren:	Fuchs, Natalie Meta, Mergim Lantzberg, Bellinda Bros, Matthias Kuan, Seah Ling Weil, Tanja Schirmeister, Tanja
Titel:	Subnanomolar cathepsin S inhibitors with high selectivity : optimizing covalent reversible α-fluorovinylsulfones and α-sulfonates as potential immunomodulators cancer
Online-Publikationsdatum:	12-Sep-2023
Erscheinungsdatum:	2023
Sprache des Dokuments:	Englisch
Zusammenfassung/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.
DDC-Sachgruppe:	540 Chemie 540 Chemistry and allied sciences 610 Medizin 610 Medical sciences
Veröffentlichende Institution:	Johannes Gutenberg-Universität Mainz
Organisationseinheit:	FB 04 Medizin FB 09 Chemie, Pharmazie u. Geowissensch.
Veröffentlichungsort:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-9524
Version:	Published version
Publikationstyp:	Zeitschriftenaufsatz
Nutzungsrechte:	CC BY
Informationen zu den Nutzungsrechten:	https://creativecommons.org/licenses/by/4.0/
Zeitschrift:	ChemMedChem 18 15
Seitenzahl oder Artikelnummer:	e202300160
Verlag:	Wiley-VCH
Verlagsort:	Weinheim
Erscheinungsdatum:	2023
ISSN:	1860-7187
DOI der Originalveröffentlichung:	10.1002/cmdc.202300160
Enthalten in den Sammlungen:	DFG-491381577-H