A Nimbolide-Based Kinase Degrader Preferentially Degrades Oncogenic BCR-ABL
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Abstract
Abstract Targeted protein degradation (TPD) and proteolysis-targeting chimeras (PROTACs) have arisen as powerful therapeutic modalities for degrading specific protein targets in a proteasome-dependent manner. However, a major limitation to broader TPD applications is the lack of E3 ligase recruiters. Recently, we discovered the natural product nimbolide as a covalent ligand for the E3 ligase RNF114. When linked to the BET family inhibitor JQ1, the resulting heterobifunctional PROTAC molecule was capable of selectively degrading BRD4 in cancer cells. Here, we show the broader utility of nimbolide as an E3 ligase recruiter for TPD applications. We demonstrate that a PROTAC linking nimbolide to the kinase and BCR-ABL fusion oncogene inhibitor dasatinib, BT1, selectively degrades BCR-ABL over c-ABL in leukemia cancer cells, compared to previously reported cereblon or VHL-recruiting BCR-ABL degraders that show opposite selectivity or in some cases inactivity. Further contrasting from cereblon or VHL-recruiting degradation, we show that BT1 treatment not only leads to BCR-ABL degradation, but also stabilizes the endogenous RNF114 substrate and tumor suppressor substrate p21. This leads to additional anti-proliferative effects in leukemia cancer cells beyond those observed with cereblon or VHL-recruiting BCR-ABL PROTACs. Thus, we further establish nimbolide as an additional general E3 ligase recruiter for PROTACs with unique additional benefits for oncology applications. We also further demonstrate the importance of expanding upon the arsenal of E3 ligase recruiters, as such molecules confer differing and unpredictable selectivity for the degradation of neo-substrate proteins.
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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 [135]
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- Authors
- Tong, B., Spradlin, J. N., Novaes, L. F. T., Zhang, E., Hu, X., Moeller, M., Brittain, S. M., McGregor, L. M., McKenna, J. M., Tallarico, J. A., Schirle, M., Maimone, T. J., & Nomura, D. K.
- Affiliations
- University of California, Berkeley (US)
- Innovative Genomics Institute (US)
- Corresponding author
- Maimone, Thomas J.
- Nomura, Daniel K.
- ORCID
- Venue
- ACS Chemical Biology
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-06-22
- Volume
- 15
- Issue
- 7
- Pages
- 1788-1794
- ISSN
- 1554-8929 (ISSN-L)
- 1554-8937
- PMC
- PMC7891886
- OpenAlex
- W3036563774
- Cited by
- 118
- References
- 36
- Citations by year
- 2026: 9 · 2025: 22 · 2024: 18 · 2023: 11 · 2022: 29 · 2021: 23 · 2020: 6
- FWCI
- 5.73
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- ACS Chemical Biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (F31CA239327, R01CA240981)
- Mark Foundation For Cancer Research
- Novartis-Berkeley Center for Proteomics and Chemistry Technologies, University of California, San Francisco
- Novartis Institutes for BioMedical Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- nimbolide, PROTACs, targeted protein degradation, RNF114, BCR-ABL, dasatinib, c-Abl, leukemia, substrate specificity, covalent ligands
- MeSH terms
- Humans, Thiazoles, Fusion Proteins, bcr-abl, K562 Cells, Limonins, Ubiquitin-Protein Ligases, Protein Kinase Inhibitors, Proteolysis
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