Development of an N-Terminal BRD4 Bromodomain-Targeted Degrader

Anand Divakaran; Cole R Scholtz; Huda Zahid; Wenwei Lin; Elizabeth C. Griffith; Richard E. Lee; Taosheng Chen; Daniel A. Harki; William C.K. Pomerantz

doi:10.1021/acsmedchemlett.2c00300

Development of an N-Terminal BRD4 Bromodomain-Targeted Degrader

Anand Divakaran, Cole R Scholtz, Huda Zahid, Wenwei Lin, Elizabeth C. Griffith, Richard E. Lee, Taosheng Chen, Daniel A. Harki, William C.K. Pomerantz

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1621-1627
Number of pages	7
Journal	ACS Medicinal Chemistry Letters
Volume	13
Issue number	10
DOIs	https://doi.org/10.1021/acsmedchemlett.2c00300
State	Published - Oct 13 2022

Bibliographical note

Funding Information:
This research was supported by the National Institutes of Health’s National Center for Advancing Translational Sciences, Grant UL1TR002494. A.D. was supported by the UMN Doctoral Dissertation Fellowship and an NIH chemistry–biology interface training grant (Grant T32-GM008700/T32-GM132029-01). H.Z. was supported by UMN IEM Engineering in Medicine Doctoral Fellowship 2020. C.R.S. was supported by the NIH Biotechnology Training Grant NIH T32GM008347. D.A.H. acknowledges funding from the Masonic Cancer Center at the University of Minnesota with resources from Minnesota Masonic Charities. T.C. is supported by National Institute of General Medical Sciences of the National Institutes of Health under Award R35GM118041.

Publisher Copyright:
© 2022 American Chemical Society.

Keywords

BET domain selectivity
BRD4 degrader
BRD4-BD1 inhibitor
epigenetic reader domain

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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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note = "Funding Information: This research was supported by the National Institutes of Health{\textquoteright}s National Center for Advancing Translational Sciences, Grant UL1TR002494. A.D. was supported by the UMN Doctoral Dissertation Fellowship and an NIH chemistry–biology interface training grant (Grant T32-GM008700/T32-GM132029-01). H.Z. was supported by UMN IEM Engineering in Medicine Doctoral Fellowship 2020. C.R.S. was supported by the NIH Biotechnology Training Grant NIH T32GM008347. D.A.H. acknowledges funding from the Masonic Cancer Center at the University of Minnesota with resources from Minnesota Masonic Charities. T.C. is supported by National Institute of General Medical Sciences of the National Institutes of Health under Award R35GM118041. Publisher Copyright: {\textcopyright} 2022 American Chemical Society.",

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AU - Lee, Richard E.

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AU - Pomerantz, William C.K.

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Development of an N-Terminal BRD4 Bromodomain-Targeted Degrader

Abstract

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