jq1-compound and Prostatic-Neoplasms--Castration-Resistant

The bromodomain and extra-terminal (BET) family proteins have gained increasing interest as drug targets for treatment of castration-resistant prostate cancer (CRPC). Here, we describe the design, optimization, and evaluation of benzo[ d]isoxazole-containing compounds as potent BET bromodomain inhibitors. Cocrystal structures of the representative inhibitors in complex with BRD4(1) provided solid structural basis for compound optimization. The two most potent compounds, 6i (Y06036) and 7m (Y06137), bound to the BRD4(1) bromodomain with K

Topics: Animals; Antineoplastic Agents; Cell Cycle Proteins; Cell Division; Drug Design; Drug Discovery; Gene Expression Regulation, Neoplastic; Humans; Isoxazoles; Male; Mice; Models, Molecular; Nuclear Proteins; Prostatic Neoplasms, Castration-Resistant; Proteins; Structure-Activity Relationship; Substrate Specificity; Transcription Factors; Tumor Stem Cell Assay; Xenograft Model Antitumor Assays

The bromodomain and extra-terminal proteins (BET) have emerged as promising therapeutic targets for the treatment of castration-resistant prostate cancer (CRPC). We report the design, synthesis and evaluation of a new series of benzoxazinone-containing 3,5-dimethylisoxazole derivatives as selective BET inhibitors. One of the new compounds, (R)-12 (Y02234), binds to BRD4(1) with a K

Topics: Animals; Antineoplastic Agents; Benzoxazines; Cell Movement; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Isoxazoles; Male; Molecular Structure; Prostatic Neoplasms, Castration-Resistant; Proteins; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Tumor Cells, Cultured