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
  • 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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