期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 143, 期 37, 页码 15073-15083出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.1c04841
关键词
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资金
- US National Institutes of Health [R01CA218600, R01CA230854, R01CA260666, R01GM122749, P30CA196521]
- Icahn School of Medicine at Mount Sinai
- National Institutes of Health SIG [1S10OD025132-01A1]
PROTACs are a promising new therapeutic modality that utilize a limited number of E3 ligases for selective protein degradation. This study demonstrates that the KEAP1 E3 ligase can be utilized to generate highly selective PROTACs, expanding the toolbox for targeted protein degradation.
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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