Subnanomolar Cathepsin S Inhibitors with High Selectivity: Optimizing Covalent Reversible α-Fluorovinylsulfones and α-Sulfonates as Potential Immunomodulators in Cancer.
cathepsins
inhibitors
molecular docking
structure-activity relationship
tumor microenvironment
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
01 08 2023
01 08 2023
Historique:
revised:
18
05
2023
received:
21
03
2023
medline:
2
8
2023
pubmed:
24
5
2023
entrez:
24
5
2023
Statut:
ppublish
Résumé
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 (K
Identifiants
pubmed: 37222230
doi: 10.1002/cmdc.202300160
doi:
Substances chimiques
cathepsin S
EC 3.4.22.27
Cathepsins
EC 3.4.-
Cathepsin L
EC 3.4.22.15
Cathepsin B
EC 3.4.22.1
Immunologic Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e202300160Informations de copyright
© 2023 The Authors. ChemMedChem published by Wiley-VCH GmbH.
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