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

Autor: Spradlin JN; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA., Hu X; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA., Ward CC; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA., Brittain SM; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Jones MD; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Ou L; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA., To M; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA., Proudfoot A; Novartis Institutes for BioMedical Research, Emeryville, CA, USA., Ornelas E; Novartis Institutes for BioMedical Research, Emeryville, CA, USA., Woldegiorgis M; Novartis Institutes for BioMedical Research, Emeryville, CA, USA., Olzmann JA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA.; Chan Zuckerberg Biohub, San Francisco, CA, USA., Bussiere DE; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Novartis Institutes for BioMedical Research, Emeryville, CA, USA., Thomas JR; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Novartis Institutes for BioMedical Research, Cambridge, MA, USA.; Vertex Pharmaceuticals, Boston, MA, USA., Tallarico JA; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., McKenna JM; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Schirle M; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Maimone TJ; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA. maimone@berkeley.edu.; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA. maimone@berkeley.edu., Nomura DK; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA. dnomura@berkeley.edu.; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA. dnomura@berkeley.edu.; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA. dnomura@berkeley.edu.; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA. dnomura@berkeley.edu.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2019 Jul; Vol. 15 (7), pp. 747-755. Date of Electronic Publication: 2019 Jun 17.
DOI: 10.1038/s41589-019-0304-8
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz: