Harnessing the E3 Ligase KEAP1 for Targeted Protein Degradation
- 14 September 2021
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 143 (37), 15073-15083
- https://doi.org/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.Keywords
Funding Information
- National Cancer Institute (P30CA196521, R01CA218600, R01CA230854, R01CA260666, R01GM122749)
- National Institute of General Medical Sciences (R01GM122749)
This publication has 29 references indexed in Scilit:
- Phthalimide conjugation as a strategy for in vivo target protein degradationScience, 2015
- Catalytic in vivo protein knockdown by small-molecule PROTACsNature Chemical Biology, 2015
- Inhibition of bromodomain and extra-terminal proteins (BET) as a potential therapeutic approach in haematological malignancies: emerging preclinical and clinical evidenceTherapeutic Advances in Hematology, 2015
- Structure of the BTB Domain of Keap1 and Its Interaction with the Triterpenoid Antagonist CDDOPLOS ONE, 2014
- The emerging family of CULLIN3-RING ubiquitin ligases (CRL3s): cellular functions and disease implicationsThe EMBO Journal, 2013
- BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-MycCell, 2011
- Proteomic Analysis Shows Synthetic Oleanane Triterpenoid Binds to mTORPLOS ONE, 2011
- Selective inhibition of BET bromodomainsNature, 2010
- Keap1 Recruits Neh2 through Binding to ETGE and DLG Motifs: Characterization of the Two-Site Molecular Recognition ModelMolecular and Cellular Biology, 2006
- Keap1 Is a Redox-Regulated Substrate Adaptor Protein for a Cul3-Dependent Ubiquitin Ligase ComplexMolecular and Cellular Biology, 2004