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Discovery of a Class of Potent and Selective Non‐competitive Sentrin‐Specific Protease 1 Inhibitors
Author(s) -
Lindenmann Urs,
Brand Michael,
Gall Flavio,
Frasson David,
Hunziker Lukas,
Kroslakova Ivana,
Sievers Martin,
Riedl Rainer
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000067
Subject(s) - allosteric regulation , proteases , prostate cancer , drug discovery , biochemistry , chemistry , metastasis , protease , in vitro , biology , cancer research , cancer , enzyme , genetics
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.