TY - JOUR
T1 - Targeted Protein Degradation by Electrophilic PROTACs that Stereoselectively and Site-Specifically Engage DCAF1
AU - Tao, Yongfeng
AU - Remillard, David
AU - Vinogradova, Ekaterina V.
AU - Yokoyama, Minoru
AU - Banchenko, Sofia
AU - Schwefel, David
AU - Melillo, Bruno
AU - Schreiber, Stuart L.
AU - Zhang, Xiaoyu
AU - Cravatt, Benjamin F.
N1 - Funding Information:
This work was supported by the NIH (AI142784 and CA231991). X.Z. was supported by NIH–NCI (R00CA248715) and the Damon-Runyon Cancer Research Foundation (DFS-53-22). D.S. was supported by the German Research Foundation (DFG) Emmy Noether Programme (SCHW1851/1-1) and by an EMBO Advanced grant (aALTF-1650).
Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/10/12
Y1 - 2022/10/12
N2 - Targeted protein degradation induced by heterobifunctional compounds and molecular glues presents an exciting avenue for chemical probe and drug discovery. 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. 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. 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 show that this process is stereoselective and does not occur in cells expressing a C1113A mutant of DCAF1. Mechanistic studies indicate that only low fractional engagement of DCAF1 is required to support protein degradation by electrophilic PROTACs. 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.
AB - Targeted protein degradation induced by heterobifunctional compounds and molecular glues presents an exciting avenue for chemical probe and drug discovery. 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. 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. 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 show that this process is stereoselective and does not occur in cells expressing a C1113A mutant of DCAF1. Mechanistic studies indicate that only low fractional engagement of DCAF1 is required to support protein degradation by electrophilic PROTACs. 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.
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U2 - 10.1021/jacs.2c08964
DO - 10.1021/jacs.2c08964
M3 - Article
C2 - 36170674
AN - SCOPUS:85139242213
SN - 0002-7863
VL - 144
SP - 18688
EP - 18699
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 40
ER -