Journal Article

Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16

Dix, Melissa M., Wucherpfennig, Thomas G., Cravatt, Benjamin F., Crowley, Vincent M., Zhang, Xiaoyu

2019

Overview

Ligand-dependent protein degradation has emerged as a compelling strategy to pharmacologically control the protein content of cells. So far, however, only a limited number of E3 ligases have been found to support this process. Here, we use a chemical proteomic strategy that leverages broadly reactive, cysteine-directed electrophilic fragments coupled to selective ligands for intracellular proteins (for example, SLF for FKBP12, JQ1 for BRD4) to screen for heterobifunctional degrader compounds (or proteolysis targeting chimeras, PROTACs) that operate by covalent adduction of E3 ligases. This approach identified DCAF16—a poorly characterized substrate recognition component of CUL4-DDB1 E3 ubiquitin ligases—as a target of electrophilic PROTACs that promote the nuclear-restricted degradation of proteins. We find that only a modest fraction (~10–40%) of DCAF16 needs to be modified to support protein degradation, pointing to the potential for electrophilic PROTACs to induce neosubstrate degradation without substantially perturbing the function of the participating E3 ligase. A chemical proteomics strategy identifies DCAF16 as a potential ubiquitin ligase recruiter for cysteine-directed electrophilic PROTACs to promote the degradation of nuclear proteins.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/92/475 / 631/92/613 / 631/92/96 / Biochemical Engineering / Biochemistry / Biodegradation / Bioorganic Chemistry / Cell Biology / Chemistry / Chemistry and Materials Science / Chemistry/Food Science / Chimeras / Degradation / Dose-Response Relationship, Drug / HEK293 Cells / Humans / Ligands / Molecular Structure / Nuclear Proteins - metabolism / Organic chemistry / Pharmacology / Protein Kinase Inhibitors - chemistry / Protein Kinase Inhibitors - pharmacology / Proteins / Proteolysis / Proteolysis - drug effects / Structure-Activity Relationship / Substrates / Ubiquitin / Ubiquitin-protein ligase