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Selective N‐Terminal BET Bromodomain Inhibitors by Targeting Non‐Conserved Residues and Structured Water Displacement **
Author(s) -
Cui Huarui,
Divakaran Anand,
Pandey Anil K.,
Johnson Jorden A.,
Zahid Huda,
Hoell Zachariah J.,
Ellingson Mikael O.,
Shi Ke,
Aihara Hideki,
Harki Daniel A.,
Pomerantz William C. K.
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202008625
Subject(s) - bromodomain , brd4 , chemistry , binding site , downregulation and upregulation , enhancer , biochemistry , gene , biology , biophysics , gene expression , acetylation
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.