Title: Harnessing the anti-cancer natural product nimbolide for targeted protein degradation.
Authors: Spradlin, Jessica N; Hu, Xirui; Ward, Carl C; Brittain, Scott M; Jones, Michael D; Ou, Lisha; To, Milton; Proudfoot, Andrew; Ornelas, Elizabeth; Woldegiorgis, Mikias; Olzmann, James A; Bussiere, Dirksen E; Thomas, Jason R; Tallarico, John A; McKenna, Jeffrey M; Schirle, Markus; Maimone, Thomas J; Nomura, Daniel K
Published In Nat Chem Biol, (2019 07)
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.
PubMed ID: 31209351
MeSH Terms: Antineoplastic Agents, Phytogenic/chemistry; Antineoplastic Agents, Phytogenic/isolation & purification; Antineoplastic Agents, Phytogenic/pharmacology*; Biological Products/chemistry; Biological Products/isolation & purification; Biological Products/pharmacology*; Breast Neoplasms/drug therapy*; Breast Neoplasms/metabolism*; Breast Neoplasms/pathology; Carrier Proteins/metabolism*; Cell Proliferation/drug effects; Drug Screening Assays, Antitumor; Female; Humans; Limonins/chemistry; Limonins/isolation & purification; Limonins/pharmacology*; Proteolysis/drug effects*; Ubiquitin-Protein Ligases