2. Academic Validation
  3. Harnessing the E3 Ligase KEAP1 for Targeted Protein Degradation

Harnessing the E3 Ligase KEAP1 for Targeted Protein Degradation

  • J Am Chem Soc. 2021 Sep 22;143(37):15073-15083. doi: 10.1021/jacs.1c04841.
Jieli Wei 1,  Fanye Meng 1,  Kwang-Su Park 1,  Hyerin Yim 1,  Julia Velez 1,  Prashasti Kumar 1,  Li Wang 2,  Ling Xie 2,  He Chen 1,  Yudao Shen 1,  Emily Teichman 1,  Dongxu Li 2 3,  Gang Greg Wang 2 3,  Xian Chen 2,  H Ümit Kaniskan 1,  Jian Jin 1
Affiliations

Affiliations

  • 1 Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 2 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 3 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
PMID: 34520194 DOI: 10.1021/jacs.1c04841
Abstract

Proteolysis targeting chimeras (PROTACs) represent a new class of promising therapeutic modalities. PROTACs hijack E3 Ligases and the ubiquitin-proteasome system (UPS), leading to selective degradation of the target proteins. However, only a very limited number of E3 Ligases have been leveraged to generate effective PROTACs. Herein, we report that the KEAP1 E3 Ligase can be harnessed for targeted protein degradation utilizing a highly selective, noncovalent small-molecule KEAP1 binder. We generated a proof-of-concept PROTAC, MS83, by linking the KEAP1 ligand to a BRD4/3/2 binder. MS83 effectively reduces protein levels of BRD4 and BRD3, but not BRD2, in cells in a concentration-, time-, KEAP1- and UPS-dependent manner. Interestingly, MS83 degrades BRD4/3 more durably than the CRBN-recruiting PROTAC dBET1 in MDA-MB-468 cells and selectively degrades BRD4 short isoform over long isoform in MDA-MB-231 cells. It also displays improved antiproliferative activity than dBET1. Overall, our study expands the limited toolbox for targeted protein degradation.

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