King, Elizabeth A., Cho, Yoojin, Dovala, Dustin, McKenna, Jeffrey, Tallarico, John, Schirle, Markus and Nomura, Daniel K. (2023) Chemoproteomics-enabled discovery of a covalent molecular glue degrader targeting NF-κB. Cell chemical biology, 30 (4). 394-402.e9. ISSN 2451-9448

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.

Item Type:	Article
Keywords:	NF-kappa B Ligands Proteomics Proteolysis Proteasome Endopeptidase Complex Ubiquitin-Protein Ligases
Date Deposited:	19 Dec 2023 00:45
Last Modified:	19 Dec 2023 00:45
URI:	https://oak.novartis.com/id/eprint/47487