These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
Tong Luo Maimone Nomura et al 2020 ChemRxiv combined.pdf (3.37 MB)

Targeted Protein Degradation via a Covalent Reversible Degrader Based on Bardoxolone

submitted on 31.03.2020, 22:03 and posted on 02.04.2020, 09:16 by Bingqi Tong, Mai Luo, Yi Xie, Jessica Spradlin, John A. Tallarico, Jeffrey M. McKenna, Markus Schirle, Thomas J. Maimone, Daniel Nomura

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.


Novartis Institutes for BioMedical Research

Novartis-Berkeley Center for Proteomics and Chemistry Technologies

Mark Foundation for Cancer Research ASPIRE award


United States Department of Health and Human Services

Find out more...


Email Address of Submitting Author


University of California, Berkeley



ORCID For Submitting Author


Declaration of Conflict of Interest

JAT, JMM, MS are employees of Novartis Institutes for BioMedical Research. This study was funded by the Novartis Institutes for BioMedical Research and the Novartis-Berkeley Center for Proteomics and Chemistry Technologies. DKN is a co-founder, shareholder, and adviser for Artris Therapeutic and Frontier Medicines.