Discovery of a Class of Potent and Selective Non-competitive Sentrin-Specific Protease 1 Inhibitors.
drug design
drug discovery
inhibitors
medicinal chemistry
structure-activity relationships
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
20 04 2020
20 04 2020
Historique:
received:
05
02
2020
pubmed:
23
2
2020
medline:
21
5
2021
entrez:
22
2
2020
Statut:
ppublish
Résumé
Sentrin-specific proteases (SENPs) are responsible for the maturation of small ubiquitin-like modifiers (SUMOs) and the deconjugation of SUMOs from their substrate proteins. Studies on prostate cancer revealed an overexpression of SENP1, which promotes prostate cancer progression as well as metastasis. Therefore, SENP1 has been identified as a novel drug target against prostate cancer. Herein, we report the discovery and biological evaluation of potent and selective SENP1 inhibitors. A structure-activity relationship (SAR) of the newly identified pyridone scaffold revealed allosteric inhibitors with very attractive in vitro ADMET properties regarding plasma binding and plasma stability for this challenging target. This study also emphasizes the importance of biochemical mode of inhibition studies for de novo designed inhibitors.
Identifiants
pubmed: 32083799
doi: 10.1002/cmdc.202000067
doi:
Substances chimiques
Protease Inhibitors
0
SENP1 protein, human
EC 3.4.-
Cysteine Endopeptidases
EC 3.4.22.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
675-679Informations de copyright
© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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