Chemoproteomics-enabled discovery of a covalent molecular glue degrader targeting NF-κB

  • Cell Chem Biol. 2023 Apr 20;30(4):394-402.e9. doi: 10.1016/j.chembiol.2023.02.008.
Elizabeth A King  1 ,  Yoojin Cho  1 ,  Nathan S Hsu  1 ,  Dustin Dovala  2 ,  Jeffrey M McKenna  3 ,  John A Tallarico  3 ,  Markus Schirle  3 ,  Daniel K Nomura  4
Affiliations
  • 1. Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA 94720, USA; Innovative Genomics Institute, Berkeley, CA 94704, USA.
  • 2. Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA 94720, USA; Novartis Institutes for BioMedical Research, Emeryville, CA 94608, USA.
  • 3. Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA 94720, USA; Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
  • 4. Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA 94720, USA; Innovative Genomics Institute, Berkeley, CA 94704, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: [email protected].
PMID: 36898369 DOI: 10.1016/j.chembiol.2023.02.008
Abstract

Targeted protein degradation has arisen as a powerful therapeutic modality for degrading disease targets. While proteolysis-targeting chimera (PROTAC) design is more modular, the discovery of molecular glue degraders has been more challenging. Here, we have coupled the phenotypic screening of a covalent ligand library with chemoproteomic approaches to rapidly discover a covalent molecular glue degrader and associated mechanisms. We have identified a cysteine-reactive covalent ligand EN450 that impairs leukemia cell viability in a NEDDylation and proteasome-dependent manner. Chemoproteomic profiling revealed covalent interaction of EN450 with an allosteric C111 in the E2 ubiquitin-conjugating enzyme UBE2D. Quantitative proteomic profiling revealed the degradation of the oncogenic transcription factor NFKB1 as a putative degradation target. Our study thus puts forth the discovery of a covalent molecular glue degrader that uniquely induced the proximity of an E2 with a transcription factor to induce its degradation in Cancer cells.

Keywords
E2 ligase; NFKB1; UBE2D; activity-based protein profiling; molecular glue; targeted protein degradation; transcription factor.
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