Structural Basis for BD1-Preferring 2,4-Disubstituted Pyrimidine BRDT Inhibitors

  • J Med Chem. 2026 May 14;69(9):11088-11108. doi: 10.1021/acs.jmedchem.6c00180.
Taimeng Liang  1 ,  Xianghong Guan  2 ,  Alice Chan  3 ,  Prakriti Kalra  1 ,  Rui Shi  2 ,  Jonathan Solberg  2 ,  Logan H Sigua  4 ,  Jun Qi  4 ,  William C K Pomerantz  1 ,  Ernst Schönbrunn  3 ,  Jon E Hawkinson  2 ,  Gunda I Georg  2
Affiliations
  • 1. Department of Chemistry, University of Minnesota, 207 Pleasant Street, SE, Minneapolis, Minnesota 55455-0431, United States.
  • 2. Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, University of Minnesota College of Pharmacy, 717 Delaware Street, SE, Minneapolis, Minnesota 55414, United States.
  • 3. Drug Discovery Department, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, Florida 33612, United States.
  • 4. Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, 360 Longwood Avenue, Boston, Massachusetts 02215, United States.
PMID: 41984625 DOI: 10.1021/acs.jmedchem.6c00180
Abstract

The first bromodomain of the BET protein BRDT (BRDT-BD1) possesses a unique Arg54 residue at the terminus of the ZA channel, absent in Other BET family members. We explored this structural uniqueness with 23 analogs of the BET/kinase inhibitor SG3-179, each bearing an amino acid side chain to enable potential interactions between the positively charged arginine group and the negatively charged carboxylate groups. In an AlphaScreen assay, serine analog 13 showed 35-fold selectivity for BRDT-T over BRD4-T. The BRDT-BD1 cocrystal structure with glutamic acid analog 14 showed no interaction with Arg54, suggesting that the observed preference may be related to differences in the structured water molecules. Compound 13 displayed exceptional in vitro metabolic stability but had limited cellular permeability in MDCK-MDR1 cells. Compounds 13 and 14 are among the best BRDT-BD1-preferring inhibitors reported to date and demonstrate a significant step toward identifying highly selective BRDT inhibitors for male contraception.

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