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
  • 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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