2. Academic Validation
  3. Development of an N-Terminal BRD4 Bromodomain-Targeted Degrader

Development of an N-Terminal BRD4 Bromodomain-Targeted Degrader

  • ACS Med Chem Lett. 2022 Sep 29;13(10):1621-1627. doi: 10.1021/acsmedchemlett.2c00300.
Anand Divakaran 1,  Cole R Scholtz 2,  Huda Zahid 2,  Wenwei Lin 3,  Elizabeth C Griffith 3,  Richard E Lee 3,  Taosheng Chen 3,  Daniel A Harki 1 2,  William C K Pomerantz 2 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, University of Minnesota, 2231 Sixth Street SE, Minneapolis, Minnesota 55455, United States.
  • 2 Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.
  • 3 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
PMID: 36262390 DOI: 10.1021/acsmedchemlett.2c00300
Abstract

Targeted protein degradation is a powerful induced-proximity tool to control cellular protein concentrations using small molecules. However, the design of selective degraders remains empirical. Among bromodomain and extra-terminal (BET) family proteins, BRD4 is the primary therapeutic target over family members BRD2/3/T. Existing strategies for selective BRD4 degradation use pan-BET inhibitors optimized for BRD4:E3 ubiquitin ligase (E3) ternary complex formation, but these result in residual inhibition of undegraded BET-bromodomains by the pan-BET ligand, obscuring BRD4-degradation phenotypes. Using our selective inhibitor of the first BRD4 bromodomain, iBRD4-BD1 (IC50 = 12 nM, 23- to 6200-fold intra-BET selectivity), we developed dBRD4-BD1 to selectively degrade BRD4 (DC50 = 280 nM). Notably, dBRD4-BD1 upregulates BRD2/3, a result not observed with degraders using pan-BET ligands. Designing BRD4 selectivity up front enables analysis of BRD4 biology without wider BET-inhibition and simplifies designing BRD4-selective heterobifunctional molecules, such as degraders with new E3 recruiting ligands or for additional probes beyond degraders.

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