2. Academic Validation
  3. A Structure-based Design Approach for Generating High Affinity BRD4 D1-Selective Chemical Probes

A Structure-based Design Approach for Generating High Affinity BRD4 D1-Selective Chemical Probes

  • J Med Chem. 2022 Feb 10;65(3):2342-2360. doi: 10.1021/acs.jmedchem.1c01779.
Huarui Cui 1,  Anand Divakaran 2,  Zachariah J Hoell 1,  Mikael O Ellingson 1,  Cole R Scholtz 1,  Huda Zahid 1,  Jorden A Johnson 1,  Elizabeth C Griffith 3,  Clifford T Gee 3,  Amani L Lee 4,  Shalil Khanal 4,  Ke Shi 5,  Hideki Aihara 5,  Vijay H Shah 4,  Richard E Lee 3,  Daniel A Harki 1 2,  William C K Pomerantz 1 2
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.
  • 2 Department of Medicinal Chemistry, University of Minnesota, 2231 Sixth Street SE, Minneapolis, Minnesota 55455, United States.
  • 3 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS1000, Memphis, Tennessee 38105, United States.
  • 4 GI Research Unit, Guggenheim 1034 Mayo Clinic, 200 First Street SW Rochester, Minnesota 55902, United States.
  • 5 Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, 321 Church Street SE, Minneapolis, Minnesota 55455, United States.
PMID: 35007061 DOI: 10.1021/acs.jmedchem.1c01779
Abstract

Chemical probes for epigenetic proteins are essential tools for dissecting the molecular mechanisms for gene regulation and therapeutic development. The bromodomain and extra-terminal (BET) proteins are master transcriptional regulators. Despite promising therapeutic targets, selective small molecule inhibitors for a single bromodomain remain an unmet goal due to their high sequence similarity. Here, we address this challenge via a structure-activity relationship study using 1,4,5-trisubstituted imidazoles against the BRD4 N-terminal bromodomain (D1). Leading compounds 26 and 30 have 15 and 18 nM affinity against BRD4 D1 and over 500-fold selectivity against BRD2 D1 and BRD4 D2 via ITC. Broader BET selectivity was confirmed by fluorescence anisotropy, thermal shift, and CETSA. Despite BRD4 engagement, BRD4 D1 inhibition was unable to reduce c-Myc expression at low concentration in multiple myeloma cells. Conversely, for inflammation, IL-8 and chemokine downregulation were observed. These results provide new design rules for selective inhibitors of an individual BET bromodomain.

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