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Bardoxolone conjugation enables targeted protein degradation of BRD4.

ABSTRACT: Targeted protein degradation (TPD) has emerged as a powerful tool in drug discovery for the perturbation of protein levels using heterobifunctional small molecules. 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.

SUBMITTER: Tong B

PROVIDER: S-EPMC7511954 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Bardoxolone conjugation enables targeted protein degradation of BRD4.

Tong Bingqi B Luo Mai M Xie Yi Y Spradlin Jessica N JN Tallarico John A JA McKenna Jeffrey M JM Schirle Markus M Maimone Thomas J TJ Nomura Daniel K DK

Scientific reports 20200923 1

Targeted protein degradation (TPD) has emerged as a powerful tool in drug discovery for the perturbation of protein levels using heterobifunctional small molecules. 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 ...[more]

PMID: 32968148

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