7ubo
Crystal Structure of the first bromodomain of human BRDT in complex with the inhibitor CCD-956
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 PubMedSignificanceBET bromodomain inhibition is therapeutic in multiple diseases; however, pan-BET inhibitors have induced significant myelosuppression and gastrointestinal toxicity, perhaps due to inhibition of both tandem bromodomains (BD) of all BET family members. However, selective inhibition of just the first BD (BD1) phenocopies pan-BET inhibitor activity in preclinical models of cancer, other diseases, and, for BRDT, in the testes for a contraceptive effect. Here, we leveraged our multibillion-molecule collection of DNA-encoded chemical libraries (DECLs) to identify BET BD1-selective inhibitors of specific chirality with high potency, stability, and good cellular activity. Our findings highlight the robustness and efficiency of the DECL platform to identify specific, potent protein binders that have promise as potential anticancer and anti-inflammatory agents and as male contraceptives. Discovery of potent BET bromodomain 1 stereoselective inhibitors using DNA-encoded chemical library selections.,Modukuri RK, Yu Z, Tan Z, Ta HM, Ucisik MN, Jin Z, Anglin JL, Sharma KL, Nyshadham P, Li F, Riehle K, Faver JC, Duong K, Nagarajan S, Simmons N, Palmer SS, Teng M, Young DW, Yi JS, Kim C, Matzuk MM Proc Natl Acad Sci U S A. 2022 May 31;119(22):e2122506119. doi:, 10.1073/pnas.2122506119. Epub 2022 May 27. PMID:35622893[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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