McKenna, Jeffrey, Tallarico, John, Schirle, Markus, Tong, Bingqi, Luo, Mai, Xie, Yi, Spradlin, Jessica, Maimone, Thomas and Nomura, Daniel (2020) Targeted Protein Degradation via a Covalent Reversible Degrader Based on Bardoxolone. Sci Rep.

Abstract

Targeted protein degradation (TPD) has emerged as a powerful tool in drug discovery for the perturbation of protein levels using heterobifunctional small molecules (i.e. PROTACs). E3 ligase recruiters remain central to this process yet relatively few have been identified relative to the >600 predicted human E3 ligases. While, initial recruiters have utilized non-covalent chemistry for protein binding, very recently covalent engagement to novel E3’s has proven fruitful in TPD application. Herein we demonstrate efficient proteasome-mediated degradation of BRD4 by a bifunctional small molecule linking the KEAP1-NRF2 activator bardoxolone to a BRD4 inhibitor JQ1. Notably, this work reports the first covalent, reversible E3 ligase recruiter for TPD applications.

Item Type:	Article
Date Deposited:	29 Jan 2021 00:45
Last Modified:	29 Jan 2021 00:45
URI:	https://oak.novartis.com/id/eprint/42532