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Harnessing the anti-cancer natural product nimbolide for targeted protein degradation

Spradlin, Jessica N. and Hu, Xirui and Ward, Carl C. and Brittain, Scott and Jones, Michael and Ou, Lisha and To, Milton and Proudfoot, Andrew and Ornelas, Elizabeth and Woldegiorgis, Mikias and Olzmann, James A. and Bussiere, Dirksen and Thomas, Jason and Tallarico, John and McKenna, Jeffrey and Schirle, Markus and Maimone, Thomas J. and Nomura, Daniel K. (2019) Harnessing the anti-cancer natural product nimbolide for targeted protein degradation. Nature Chemical Biology, 15 (7). pp. 747-755. ISSN 15524469

Abstract

Nimbolide, a terpenoid natural product derived from the Neem tree, impairs cancer pathogenicity; however, the direct targets and mechanisms by which nimbolide exerts its effects are poorly understood. Here, we used activity-based protein profiling (ABPP) chemoproteomic platforms to discover that nimbolide reacts with a novel functional cysteine crucial for substrate recognition in the E3 ubiquitin ligase RNF114. Nimbolide impairs breast cancer cell proliferation in-part by disrupting RNF114-substrate recognition, leading to inhibition of ubiquitination and degradation of tumor suppressors such as p21, resulting in their rapid stabilization. We further demonstrate that nimbolide can be harnessed to recruit RNF114 as an E3 ligase in targeted protein degradation applications and show that synthetically simpler scaffolds are also capable of accessing this unique reactive site. Our study highlights the use of ABPP platforms in uncovering unique druggable modalities accessed by natural products for cancer therapy and targeted protein degradation applications.

Item Type: Article
Date Deposited: 20 Aug 2019 00:45
Last Modified: 20 Aug 2019 00:45
URI: https://oak.novartis.com/id/eprint/37517

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