Harnessing the anti-cancer natural product nimbolide for targeted protein degradation
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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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Covalent drug discovery platforms have facilitated expansion of targeted protein degradation by enabling discovery of covalent recruiters against E3 ubiquitin ligases.
“Covalent drug discovery platforms have facilitated the expansion of targeted protein degradation approaches by enabling the discovery of covalent recruiters against E3 ubiquitin ligases14,187–193.”
From Advances in covalent drug discovery (2022) · cites this paper as [187]
Since 2019, covalent recruiters have been used to validate a large proportion of E3 ligases harnessed for targeted protein degradation, including RNF114, RNF4, DCAF16, DCAF11, KEAP1 and FEM1B.
“Since 2019, covalent recruiters have been used to validate a large proportion of the E3 ligases that have been harnessed for targeted protein degradation, including RING finger protein 114 (RNF114), RNF4, DDB1 and CUL4-associated factor 16 (DCAF16), DCAF11, KEAP1 and, most recently, fem-1 homologue B (FEM1B)187–193.”
From Advances in covalent drug discovery (2022) · cites this paper as [187]
This enabled design of RNF114-based degraders, expanding to other chemotypes.
“This enabled the design of RNF114-based degraders, also expanding to other chemotypes.84,85”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [84]
Additional generic E3 ligases (RNF4, RNF114, KEAP1, FEM1B) have been shown to be exploitable by PROTACs using small-molecule covalent tools to degrade BRD4.
“a few additional ‘generic’ E3 ligases have been shown to be exploitable by PROTACs, using small-molecule covalent tools that specifically recruit the ligases to degrade the prototypical TPD substrate, BRD4; these ligases include ring finger protein 4 (RNF4)132, RNF114 (refs133–135), KEAP1 (refs136,137) and most recently, fem-1 homologue B (FEM1B)138.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [133]
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- Authors
- Spradlin, J. N., Hu, X., Ward, C. C., Brittain, S. M., Jones, M. D., Ou, L., To, M., Proudfoot, A., Ornelas, E., Woldegiorgis, M., Olzmann, J. A., Bussiere, D. E., Thomas, J. R., Tallarico, J. A., McKenna, J. M., Schirle, M., Maimone, T. J., & Nomura, D. K.
- Affiliations
- University of California, Berkeley (US)
- Chan Zuckerberg Biohub San Francisco (US)
- Vertex Pharmaceuticals (United States) (US)
- Corresponding author
- Maimone, Thomas J.
- Nomura, Daniel K.
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2019-06-17
- Volume
- 15
- Issue
- 7
- Pages
- 747-755
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC6592714
- OpenAlex
- W2950911502
- Cited by
- 432
- References
- 86
- Citations by year
- 2026: 49 · 2025: 61 · 2024: 63 · 2023: 56 · 2022: 69 · 2021: 66 · 2020: 47 · 2019: 21
- FWCI
- 16.88
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature Chemical Biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- The Novartis Repository (Novartis) (submittedVersion)
- Funders
- National Institutes of Health
- Novartis Institutes for BioMedical Research
- National Cancer Institute (R01CA172667, F31CA225173, F31CA239327, R01CA240981)
- National Institute of General Medical Sciences (R01GM112948)
- National Institute of Environmental Health Sciences (P42ES004705, R01ES028096)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- nimbolide, targeted protein degradation, RNF114, E3 ubiquitin ligase, substrate recognition, breast cancer, chemoproteomics, activity-based protein profiling, natural products, Azadirachta indica, ubiquitination, protein degradation
- MeSH terms
- Antineoplastic Agents, Phytogenic, Biological Products, Breast Neoplasms, Carrier Proteins, Drug Screening Assays, Antitumor, Female, Humans, Limonins, Ubiquitin-Protein Ligases, Cell Proliferation, Proteolysis
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