mdv-3100 and bicalutamide

Metastatic prostate cancer is treated with drugs that antagonize androgen action, but most patients progress to a more aggressive form of the disease called castration-resistant prostate cancer, driven by elevated expression of the androgen receptor. Here we characterize the diarylthiohydantoins RD162 and MDV3100, two compounds optimized from a screen for nonsteroidal antiandrogens that retain activity in the setting of increased androgen receptor expression. Both compounds bind to the androgen receptor with greater relative affinity than the clinically used antiandrogen bicalutamide, reduce the efficiency of its nuclear translocation, and impair both DNA binding to androgen response elements and recruitment of coactivators. RD162 and MDV3100 are orally available and induce tumor regression in mouse models of castration-resistant human prostate cancer. Of the first 30 patients treated with MDV3100 in a Phase I/II clinical trial, 13 of 30 (43%) showed sustained declines (by >50%) in serum concentrations of prostate-specific antigen, a biomarker of prostate cancer. These compounds thus appear to be promising candidates for treatment of advanced prostate cancer.

Topics: Androgen Antagonists; Anilides; Animals; Antineoplastic Agents; Benzamides; Biological Availability; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; DNA; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Receptors, Androgen; Tosyl Compounds; Transcription, Genetic; Xenograft Model Antitumor Assays

The androgen receptor (AR) is a pivotal target for the treatment of prostate cancer (PC) even when the disease progresses toward androgen-independent or castration-resistant forms. In this study, a series of sulfoxide derivatives were prepared and their antiproliferative activity evaluated in vitro against four different human prostate cancer cell lines (22Rv1, DU-145, LNCaP and VCap). Bicalutamide and enzalutamide were used as positive controls. Compound 28 displayed significant enhancement in anticancer activity across the four PC cell lines with IC

Topics: Anilides; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Male; Models, Molecular; Molecular Structure; Nitriles; Prostatic Neoplasms; Structure-Activity Relationship; Sulfoxides; Tosyl Compounds

Deshydroxy propioanilides were synthesised by Michael addition reaction between substituted thiophenols onto four different phenylacrylamide derivatives to give twenty-three novel deshydroxy bicalutamide derivatives lacking the central hydroxyl group. The antiproliferative activities of these compounds were evaluated against human prostate cancer cell lines and thirteen compounds showed better inhibitory activities (IC

Topics: Androgen Antagonists; Anilides; Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Cell Proliferation; Drug Discovery; Drug Screening Assays, Antitumor; Humans; Male; Models, Molecular; Nitriles; Prostatic Neoplasms; Tosyl Compounds

SAR studies on bicalutamide, enobosarm and enzalutamide analogues, functionalised with polyfluorinated groups, is presented. Among the novel bicalutamide and enobosarm derivatives synthesised, several displayed significantly improved in vitro anticancer activity, with IC

Topics: Anilides; Animals; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Cell Proliferation; CHO Cells; Cricetulus; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Ether-A-Go-Go Potassium Channels; Humans; Hydrocarbons, Fluorinated; Male; Mice; Mice, Nude; Molecular Structure; Neoplasms, Experimental; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Structure-Activity Relationship; Sulfhydryl Compounds; Tosyl Compounds

Prostate cancer (PC) is one of the major causes of male death worldwide and the development of new and more potent anti-PC compounds is a constant requirement. Among the current treatments, (R)-bicalutamide and enzalutamide are non-steroidal androgen receptor antagonist drugs approved also in the case of castration-resistant forms. Both these drugs present a moderate antiproliferative activity and their use is limited due to the development of resistant mutants of their biological target. Insertion of fluorinated and perfluorinated groups in biologically active compounds is a current trend in medicinal chemistry, applied to improve their efficacy and stability profiles. As a means to obtain such effects, different modifications with perfluoro groups were rationally designed on the bicalutamide and enzalutamide structures, leading to the synthesis of a series of new antiproliferative compounds. Several new analogues displayed improved in vitro activity towards four different prostate cancer cell lines, while maintaining full AR antagonism and therefore representing promising leads for further development. Furthermore, a series of molecular modelling studies were performed on the AR antagonist conformation, providing useful insights on potential protein-ligand interactions.

Topics: Anilides; Antineoplastic Agents; Benzamides; Caco-2 Cells; Cell Line, Tumor; Cell Proliferation; Chemistry Techniques, Synthetic; Drug Design; Drug Resistance, Neoplasm; Humans; Male; Microsomes, Liver; Molecular Docking Simulation; Molecular Dynamics Simulation; Nitriles; Permeability; Phenylthiohydantoin; Prostatic Neoplasms; Protein Conformation; Receptors, Androgen; Tosyl Compounds