9ycq
First Bromodomain of BRDT liganded with inhibitor GXH-IV-076 (compound 33)
Structural highlights
FunctionBRDT_HUMAN Testis-specific chromatin protein that specifically binds histone H4 acetylated at 'Lys-5' and 'Lys-8' (H4K5ac and H4K8ac, respectively) and plays a key role in spermatogenesis. Required in late pachytene spermatocytes: plays a role in meiotic and post-meiotic cells by binding to acetylated histones at the promoter of specific meiotic and post-meiotic genes, facilitating their activation at the appropriate time. In the post-meiotic phase of spermatogenesis, binds to hyperacetylated histones and participates in their general removal from DNA. Also acts as a component of the splicing machinery in pachytene spermatocytes and round spermatids and participates in 3'-UTR truncation of specific mRNAs in post-meiotic spermatids. Required for chromocenter organization, a structure comprised of peri-centromeric heterochromatin.[1] [2] [3] Publication Abstract from PubMedThe 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. Structural Basis for BD1-Preferring 2,4-Disubstituted Pyrimidine BRDT Inhibitors.,Liang T, Guan X, Chan A, Kalra P, Shi R, Solberg J, Sigua LH, Qi J, Pomerantz WCK, Schonbrunn E, Hawkinson JE, Georg GI J Med Chem. 2026 May 14;69(9):11088-11108. doi: 10.1021/acs.jmedchem.6c00180. , Epub 2026 Apr 15. PMID:41984625[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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