2. Academic Validation
  3. Chemoproteomics-enabled discovery of covalent RNF114-based degraders that mimic natural product function

Chemoproteomics-enabled discovery of covalent RNF114-based degraders that mimic natural product function

  • Cell Chem Biol. 2021 Apr 15;28(4):559-566.e15. doi: 10.1016/j.chembiol.2021.01.005.
Mai Luo 1,  Jessica N Spradlin 1,  Lydia Boike 1,  Bingqi Tong 1,  Scott M Brittain 2,  Jeffrey M McKenna 2,  John A Tallarico 2,  Markus Schirle 2,  Thomas J Maimone 3,  Daniel K Nomura 4
Affiliations

Affiliations

  • 1 Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Cambridge, MA 02139, USA.
  • 2 Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Cambridge, MA 02139, USA; Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
  • 3 Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Cambridge, MA 02139, USA. Electronic address: [email protected].
  • 4 Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Cambridge, MA 02139, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Nutritional Sciences and Toxicology, Univerity of California, Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, Berkeley, CA 94720, USA. Electronic address: [email protected].
PMID: 33513350 DOI: 10.1016/j.chembiol.2021.01.005
Abstract

The translation of functionally active Natural Products into fully synthetic small-molecule mimetics has remained an important process in medicinal chemistry. We recently discovered that the terpene natural product nimbolide can be utilized as a covalent recruiter of the E3 ubiquitin ligase RNF114 for use in targeted protein degradation-a powerful therapeutic modality within modern-day drug discovery. Using activity-based protein profiling-enabled covalent ligand-screening approaches, here we report the discovery of fully synthetic RNF114-based recruiter molecules that can also be exploited for PROTAC applications, and demonstrate their utility in degrading therapeutically relevant targets, such as BRD4 and Bcr-Abl, in cells. The identification of simple and easily manipulated drug-like scaffolds that can mimic the function of a complex natural product is beneficial in further expanding the toolbox of E3 ligase recruiters, an area of great importance in drug discovery and chemical biology.

Keywords

PROTAC; RNF114; chemoproteomics; covalent ligand; cysteine; targeted protein degradation.

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