| Literature DB >> 34520194 |
Jieli Wei1, Fanye Meng1, Kwang-Su Park1, Hyerin Yim1, Julia Velez1, Prashasti Kumar1, Li Wang2, Ling Xie2, He Chen1, Yudao Shen1, Emily Teichman1, Dongxu Li2,3, Gang Greg Wang2,3, Xian Chen2, H Ümit Kaniskan1, Jian Jin1.
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.Entities:
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Year: 2021 PMID： 34520194 PMCID： PMC8480205 DOI： 10.1021/jacs.1c04841
Source DB: PubMed Journal: J Am Chem Soc ISSN： 0002-7863 Impact factor: 16.383