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Tong Luo Maimone Nomura et al 2020 ChemRxiv combined.pdf (3.37 MB)

Targeted Protein Degradation via a Covalent Reversible Degrader Based on Bardoxolone

preprint
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.

Funding

Novartis Institutes for BioMedical Research

Novartis-Berkeley Center for Proteomics and Chemistry Technologies

Mark Foundation for Cancer Research ASPIRE award

NATIONAL INSTITUTES OF HEALTH (NIH)

United States Department of Health and Human Services

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History

Email Address of Submitting Author

dnomura@berkeley.edu

Institution

University of California, Berkeley

Country

USA

ORCID For Submitting Author

0000-0003-1614-8360

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.

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