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.

中文翻译：

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发现一类新型的有效和选择性非竞争性Sentrin特异性蛋白酶1抑制剂。

Sentrin特异性蛋白酶（SENP）负责小的泛素样修饰剂（SUMO）的成熟以及SUMO从其底物蛋白的脱结合。对前列腺癌的研究表明SENP1的过表达，可促进前列腺癌的进展以及转移。因此，SENP1已被确定为针对前列腺癌的新型药物靶标。在这里，我们报告了有效的和选择性的SENP1抑制剂的发现和生物学评估。新发现的吡啶酮支架的构效关系（SAR）显示出变构抑制剂具有极具吸引力的体外ADMET特性，涉及该挑战目标的血浆结合和血浆稳定性。该研究还强调了从头设计抑制剂的生化抑制研究模式的重要性。