![]() ![]() ![]() These findings, taken together, demonstrate how the chemical proteomic analysis of stereochemically defined electrophilic compound sets can uncover ligandable sites on E3 ligases that support targeted protein degradation. ![]() Mechanistic studies indicate that only low fractional engagement of DCAF1 is required to support protein degradation by electrophilic PROTACs. We show that this process is stereoselective and does not occur in cells expressing a C1113A mutant of DCAF1. Tao Group is now serving everywhere Ship your TAO and LAVO favorites nationwide on goldbelly Choose from our. We demonstrate that the azetidine acrylamide ligands for DCAF1 can be developed into electrophilic proteolysis-targeting chimeras (PROTACs) that mediated targeted protein degradation in human cells. We report herein the discovery by chemical proteomics of azetidine acrylamides that stereoselectively and site-specifically react with a cysteine (C1113) in the E3 ligase substrate receptor DCAF1. To date, small-molecule ligands have been discovered for only a limited number of E3 ligases, which is an important limiting factor for realizing the full potential of targeted protein degradation. Jonathan Schwartz, JD ’86, at the Univision studio in Manhattan (Photo by Ethan Hill) There is a dizzying view from the lobby of Univision’s Manhattan headquarters on the 33rd floor of a mid-town skyscrapertall windows framing the iconic skyline, the vista metaphor for the American dream that the media conglomerate has come. Targeted protein degradation induced by heterobifunctional compounds and molecular glues presents an exciting avenue for chemical probe and drug discovery.
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