Thursday, April 2, 2020

Targeted Protein Degradation via a Covalent Reversible Degrader Based on Bardoxolone [@DanNomura]

Tong, Bingqi; Luo, Mai; Xie, Yi; Spradlin, Jessica; Tallarico, John A.; McKenna, Jeffrey M. McKenna, Markus Schirle, Thomas J. Maimone, and Daniel K. Nomura

ChemRxiv. 2020
https://doi.org/10.26434/chemrxiv.12055935.v1

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 >500 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.

Oncogenic KRAS G12C: Kinetic and Redox Characterization of Covalent Inhibition

Minh V. Huynh, Derek Parsonage, Tom E. Forshaw, Venkat R. Chirasani, G. Aaron Hobbs, Hanzhi Wu, Jingyun Lee, Cristina M. Furdui, Leslie B. P...