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;
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- Angela F. Ku
- Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
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- Justin L. Anglin
- Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
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- Rajesh Sharma
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030;
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- Melek Nihan Ucisik
- Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
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- John C. Faver
- Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
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- Feng Li
- Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
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- Pranavanand Nyshadham
- Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
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- Nicholas Simmons
- Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
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- Kiran L. Sharma
- Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
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- Sureshbabu Nagarajan
- Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
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- Kevin Riehle
- Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
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- Gundeep Kaur
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030;
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- Banumathi Sankaran
- Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, CA 94720;
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- Marta Storl-Desmond
- Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
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- Stephen S. Palmer
- Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
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- Damian W. Young
- Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
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- Choel Kim
- Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
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- Martin M. Matzuk
- Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030;
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説明
<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>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 118 (9), 2021-02-26
Proceedings of the National Academy of Sciences