Discovery of a Class of Potent and Selective Non-competitive Sentrin-Specific Protease 1 Inhibitors |
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| Authors: | Urs Lindenmann Dr. Michael Brand Flavio Gall David Frasson Lukas Hunziker Dr. Ivana Kroslakova Prof. Dr. Martin Sievers Prof. Dr. Rainer Riedl |
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| Affiliation: | 1. Institute of Chemistry and Biotechnology, Center of Organic and Medicinal Chemistry, ZHAW Zurich University of Applied Sciences, Einsiedlerstr. 31, 8820 Wädenswil, Switzerland;2. Institute of Chemistry and Biotechnology, Center of Molecular Biology, ZHAW Zurich University of Applied Sciences, Einsiedlerstr. 31, 8820 Wädenswil, Switzerland |
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| Abstract: | 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. |
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| Keywords: | medicinal chemistry structure-activity relationships drug discovery inhibitors drug design |
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