Discovery and characterization of bromodomain 2–specific inhibitors of BRDT

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  • Zhifeng Yu
    Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
  • Angela F. Ku
    Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
  • Justin L. Anglin
    Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
  • Rajesh Sharma
    Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030;
  • Melek Nihan Ucisik
    Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
  • John C. Faver
    Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
  • Feng Li
    Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
  • Pranavanand Nyshadham
    Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
  • Nicholas Simmons
    Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
  • Kiran L. Sharma
    Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
  • Sureshbabu Nagarajan
    Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
  • Kevin Riehle
    Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
  • Gundeep Kaur
    Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030;
  • Banumathi Sankaran
    Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, CA 94720;
  • Marta Storl-Desmond
    Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
  • Stephen S. Palmer
    Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
  • Damian W. Young
    Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
  • Choel Kim
    Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
  • Martin M. Matzuk
    Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;

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<jats:title>Significance</jats:title> <jats:p>There is no nonhormonal contraceptive pill for men, although hundreds of genes have been identified to play roles during spermatogenesis and fertilization in the male reproductive tract. To address the absence of contraceptive drugs for men, we established a DNA-encoded chemistry technology (DEC-Tec) platform. Our drug discovery campaign on BRDT, a validated spermatogenic-specific contraceptive target, yielded rapid discovery of potent and specific inhibitors of the second bromodomain of BRDT that have unique binding characteristics to BRDT-BD2 relative to BRDT-BD1. Our study emphasizes the robustness and validation of the DEC-Tec platform where the obtained structure–affinity relationship data would allow us to identify specific protein binders immediately without performing exhaustive medicinal chemistry optimization of compounds with potential as male contraceptives.</jats:p>

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