Selective N-Terminal BET Bromodomain Inhibitors by Targeting Non-Conserved Residues and Structured Water Displacement**

Huarui Cui, Anand Divakaran, Anil K. Pandey, Jorden A. Johnson, Huda Zahid, Zachariah J. Hoell, Mikael O. Ellingson, Ke Shi, Hideki Aihara, Daniel A. Harki, William C.K. Pomerantz

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Bromodomain and extra-terminal (BET) family proteins, BRD2-4 and T, are important drug targets; however, the biological functions of each bromodomain remain ill-defined. Chemical probes that selectively inhibit a single BET bromodomain are lacking, although pan inhibitors of the first (D1), and second (D2), bromodomain are known. Here, we develop selective BET D1 inhibitors with preferred binding to BRD4 D1. In competitive inhibition assays, we show that our lead compound is 9–33 fold selective for BRD4 D1 over the other BET bromodomains. X-ray crystallography supports a role for the selectivity based on reorganization of a non-conserved lysine and displacement of an additional structured water in the BRD4 D1 binding site relative to our prior lead. Whereas pan-D1 inhibitors displace BRD4 from MYC enhancers, BRD4 D1 inhibition in MM.1S cells is insufficient for stopping Myc expression and may lead to its upregulation. Future analysis of BRD4 D1 gene regulation may shed light on differential BET bromodomain functions.

Original languageEnglish (US)
Pages (from-to)1220-1226
Number of pages7
JournalAngewandte Chemie - International Edition
Issue number3
StatePublished - Jan 18 2021

Bibliographical note

Funding Information:
We gratefully acknowledge support for this research from the Masonic Cancer Center at the University of Minnesota, (W.C.K.P and D.A.H) the NIH (R35‐GM118047 to H.A. and R01‐GM110129 to D.A.H), the American Heart Association (15SDG25710427 to W.C.K.P.). J.A.J. was supported by a NIH Biotechnology training grant (T32‐GM008347‐23) and A.D. was supported by the NIH chemistry‐biology interface training grant (T32‐GM008700). This work is based on research conducted at the NE‐CAT beamlines at the Advanced Photon Source, which are supported by the NIH (P30‐GM124165). The Pilatus 6M detector on 24‐ID‐C beamline is funded by a NIH‐ORIP HEI grant (S10‐RR029205). We thank staff at the NE‐CAT beamlines for assistance in data collection, Dr. Peter Ycas for help preparing the His9‐BRD4 D1 plasmid, and Dr. Brian Van Ness for providing MM.1S cells.

Publisher Copyright:
© 2020 Wiley-VCH GmbH

Copyright 2021 Elsevier B.V., All rights reserved.


  • BET bromodomains
  • BRD4 D1 selectivity
  • epigenetics
  • inhibitors
  • structure-activity relationships

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

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