Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 60, Issue 3, Pages 1220-1226Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202008625
Keywords
BET bromodomains; BRD4 D1 selectivity; epigenetics; inhibitors; structure-activity relationships
Categories
Funding
- Masonic Cancer Center at the University of Minnesota
- NIH [R35-GM118047, R01-GM110129, P30-GM124165]
- American Heart Association [15SDG25710427]
- NIH Biotechnology training grant [T32-GM008347-23]
- NIH chemistry-biology interface training grant [T32-GM008700]
- NIH-ORIP HEI grant [S10-RR029205]
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The study developed selective BET D1 inhibitors with higher selectivity for BRD4 D1, but BRD4 D1 inhibition may not be sufficient to stop Myc expression and could even lead to its upregulation. Future analysis of BRD4 D1 gene regulation may shed light on the differential functions of BET bromodomains.
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.
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