Open AccessHarnessing the E3 Ligase KEAP1 for Targeted Protein Degradation
Author(s) -
Jieli Wei,
Fei Meng,
KwangSu Park,
Hyerin Yim,
Julia Velez,
Prashasti Kumar,
Li Wang,
Ling Xie,
He Chen,
Yudao Shen,
Emily M. Teichman,
Dongxu Li,
Gang Greg Wang,
Xian Chen,
H. Ümit Kanıskan,
Jian Jin
Publication year - 2021
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.1c04841
Subject(s) - ubiquitin ligase , brd4 , keap1 , chemistry , ubiquitin , proteasome , protein degradation , gene isoform , proteolysis , microbiology and biotechnology , dna ligase , biochemistry , computational biology , bromodomain , transcription factor , dna , biology , gene , enzyme , histone
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.