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Citation
Tags
HERO ID
7099413
Reference Type
Journal Article
Title
Harnessing the anti-cancer natural product nimbolide for targeted protein degradation
Author(s)
Spradlin, JN; Hu, X; Ward, CC; Brittain, SM; Jones, MD; Ou, L; To, M; Proudfoot, A; Ornelas, E; Woldegiorgis, M; Olzmann, JA; Bussiere, DE; Thomas, , JR; Tallarico, JA; Mckenna, JM; Schirle, M; Maimone, TJ; Nomura, DK; ,
Year
2019
Is Peer Reviewed?
1
Journal
Nature Chemical Biology
ISSN:
1552-4450
EISSN:
1552-4469
Publisher
NATURE PUBLISHING GROUP
Location
NEW YORK
Page Numbers
747-+
Language
English
PMID
31209351
DOI
10.1038/s41589-019-0304-8
Web of Science Id
WOS:000472625600019
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.
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