Subnanomolar Cathepsin S Inhibitors with High Selectivity: Optimizing Covalent Reversible α-Fluorovinylsulfones and α-Sulfonates as Potential Immunomodulators in Cancer

Publikationstyp:
Zeitschriftenaufsatz
Metadaten:
Autoren
  • Natalie Fuchs
  • Mergim Meta
  • Bellinda Lantzberg
  • Matthias Bros
  • Seah Ling Kuan
  • Tanja Weil
  • Tanja Schirmeister
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000999466000001&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1002/cmdc.202300160
eISSN
1860-7187
Externe Identifier
  • Clarivate Analytics Document Solution ID: N5VY6
  • PubMed Identifier: 37222230
ISSN
1860-7179
Ausgabe der Veröffentlichung
15
Zeitschrift
CHEMMEDCHEM
Schlüsselwörter
  • cathepsins
  • inhibitors
  • molecular docking
  • structure-activity relationship
  • tumor microenvironment
Datum der Veröffentlichung
2023
Status
Published
Titel
Subnanomolar Cathepsin S Inhibitors with High Selectivity: Optimizing Covalent Reversible α-Fluorovinylsulfones and α-Sulfonates as Potential Immunomodulators in Cancer
Sub types
  • Article
Ausgabe der Zeitschrift
18

Datenquelle: Web of Science (Lite)

Andere Metadatenquellen:
Abstract
<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>α</jats:italic>‐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<jats:sub>i</jats:sub>=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.</jats:p>
Autoren
  • Natalie Fuchs
  • Mergim Meta
  • Bellinda Lantzberg
  • Matthias Bros
  • Seah Ling Kuan
  • Tanja Weil
  • Tanja Schirmeister
DOI
10.1002/cmdc.202300160
eISSN
1860-7187
ISSN
1860-7179
Ausgabe der Veröffentlichung
15
Zeitschrift
ChemMedChem
Sprache
en
Online publication date
2023
Datum der Veröffentlichung
2023
Status
Published
Herausgeber
Wiley
Herausgeber URL
http://dx.doi.org/10.1002/cmdc.202300160
Datum der Datenerfassung
2023
Titel
Subnanomolar Cathepsin S Inhibitors with High Selectivity: Optimizing Covalent Reversible α‐Fluorovinylsulfones and α‐Sulfonates as Potential Immunomodulators in Cancer
Ausgabe der Zeitschrift
18

Datenquelle: Crossref

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 (K<sub>i</sub> =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.
Addresses
  • Institute of Pharmaceutical and Biomedical Sciences (IPBS), Johannes Gutenberg University Mainz, Staudingerweg 5, 55128, Mainz, Germany.
Autoren
  • Natalie Fuchs
  • Mergim Meta
  • Bellinda Lantzberg
  • Matthias Bros
  • Seah Ling Kuan
  • Tanja Weil
  • Tanja Schirmeister
DOI
10.1002/cmdc.202300160
eISSN
1860-7187
Externe Identifier
  • PubMed Identifier: 37222230
Open access
false
ISSN
1860-7179
Ausgabe der Veröffentlichung
15
Zeitschrift
ChemMedChem
Schlüsselwörter
  • Humans
  • Neoplasms
  • Cathepsins
  • Cathepsin B
  • Immunologic Factors
  • Cathepsin L
  • Molecular Docking Simulation
Sprache
eng
Medium
Print-Electronic
Online publication date
2023
Paginierung
e202300160
Datum der Veröffentlichung
2023
Status
Published
Publisher licence
CC BY
Datum der Datenerfassung
2023
Titel
Subnanomolar Cathepsin S Inhibitors with High Selectivity: Optimizing Covalent Reversible α-Fluorovinylsulfones and α-Sulfonates as Potential Immunomodulators in Cancer.
Sub types
  • Research Support, Non-U.S. Gov't
  • Journal Article
Ausgabe der Zeitschrift
18

Datenquelle: Europe PubMed Central

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.
Autoren
  • Natalie Fuchs
  • Mergim Meta
  • Bellinda Lantzberg
  • Matthias Bros
  • Seah Ling Kuan
  • Tanja Weil
  • Tanja Schirmeister
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/37222230
DOI
10.1002/cmdc.202300160
eISSN
1860-7187
Ausgabe der Veröffentlichung
15
Zeitschrift
ChemMedChem
Schlüsselwörter
  • cathepsins
  • inhibitors
  • molecular docking
  • structure-activity relationship
  • tumor microenvironment
  • Humans
  • Molecular Docking Simulation
  • Cathepsins
  • Cathepsin L
  • Cathepsin B
  • Immunologic Factors
  • Neoplasms
Sprache
eng
Country
Germany
Paginierung
e202300160
Datum der Veröffentlichung
2023
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2023
Titel
Subnanomolar Cathepsin S Inhibitors with High Selectivity: Optimizing Covalent Reversible α-Fluorovinylsulfones and α-Sulfonates as Potential Immunomodulators in Cancer.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
18

Datenquelle: PubMed

Author's licence
CC-BY
Autoren
  • Natalie Fuchs
  • Mergim Meta
  • Bellinda Lantzberg
  • Matthias Bros
  • Seah Ling Kuan
  • Tanja Weil
  • Tanja Schirmeister
Hosting institution
Universitätsbibliothek Mainz
Sammlungen
  • DFG-491381577-H
Resource version
Published version
DOI
10.1002/cmdc.202300160
Funding acknowledgements
  • Deutsche Forschungsgemeinschaft (DFG)|491381577|Open-Access-Publikationskosten 2022–2024 Universität Mainz - Universitätsmedizin
File(s) embargoed
false
Open access
true
ISSN
1860-7187
Ausgabe der Veröffentlichung
15
Zeitschrift
ChemMedChem
Schlüsselwörter
  • 540 Chemie
  • 540 Chemistry and allied sciences
  • 610 Medizin
  • 610 Medical sciences
Sprache
eng
Open access status
Open Access
Paginierung
e202300160
Datum der Veröffentlichung
2023
Public URL
https://openscience.ub.uni-mainz.de/handle/20.500.12030/9542
Herausgeber
Wiley-VCH
Datum der Datenerfassung
2023
Datum, an dem der Datensatz öffentlich gemacht wurde
2023
Zugang
Public
Titel
Subnanomolar cathepsin S inhibitors with high selectivity : optimizing covalent reversible α-fluorovinylsulfones and α-sulfonates as potential immunomodulators cancer
Ausgabe der Zeitschrift
18

Files

subnanomolar_cathepsin_s_inhi-20230901153132231.pdf

Datenquelle: OPENSCIENCE.UB

Beziehungen:
Eigentum von

Werkzeuge