TY - JOUR
T1 - Development of an N-Terminal BRD4 Bromodomain-Targeted Degrader
AU - Divakaran, Anand
AU - Scholtz, Cole R.
AU - Zahid, Huda
AU - Lin, Wenwei
AU - Griffith, Elizabeth C.
AU - Lee, Richard E.
AU - Chen, Taosheng
AU - Harki, Daniel A.
AU - Pomerantz, William C.K.
N1 - Publisher Copyright:
© 2022 American Chemical Society.
PY - 2022/10/13
Y1 - 2022/10/13
N2 - 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.
AB - 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.
KW - BET domain selectivity
KW - BRD4 degrader
KW - BRD4-BD1 inhibitor
KW - epigenetic reader domain
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U2 - 10.1021/acsmedchemlett.2c00300
DO - 10.1021/acsmedchemlett.2c00300
M3 - Article
C2 - 36262390
AN - SCOPUS:85139417672
SN - 1948-5875
VL - 13
SP - 1621
EP - 1627
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 10
ER -