Description:
<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>in vitro</jats:italic> 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 <jats:italic>de novo</jats:italic> designed inhibitors.</jats:p>