title: Synthesis and in vitro characterization of ionone-based chalcones as novel antiandrogens effective against multiple clinically relevant androgen receptor mutants.
abstract: A crucial event in prostate cancer progression is the transition from a hormone-sensitive to a lethal castration-refractory disease state. The antagonist-to-agonist conversion due to mutation in AR is a critical problem with the current clinically used antiandrogens. We aim to identify novel antiandrogens that remain as a pure antagonist even in the mutated ARs. By synthesizing a series of ionone-based chalcones, we have identified a novel chalcone (17) that is a pan-antagonist of the wild type and the clinically relevant T877A, W741C and H874Y mutated ARs in luciferase reporter assays in PC-3 cells. Further, chalcone 17 demonstrates sub-micromolar to low micromolar antiproliferative activity in LNCaP, MDA-PCa-2b, 22Rv1 and C4-2B prostate cancer cells, all of which express mutated ARs and confer resistance to the current clinically used antiandrogens. The results suggest that chalcone 17 could be a good candidate for further pre-clinical development as a novel antiandrogen for advanced prostate cancer.
authors.affiliation: Segal Cancer Center, Sir Mortimer B Davis-Jewish General Hospital, 3755 Cote-Ste-Catherine Rd., Montreal, QC H3T 1E2, Canada.
authors.forename: Jinming
authors.initials: J
authors.lastname: Zhou
authors.forename: Guoyan
authors.initials: G
authors.lastname: Geng
authors.forename: Jian Hui
authors.initials: JH
authors.lastname: Wu
mesh_terms: D000726:Androgen Antagonists / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D059002:Androgen Receptor Antagonists; D018931:Antineoplastic Agents, Hormonal / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047188:Chalcones / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D015394:Molecular Structure; D009154:Mutation / Q000187:drug effects*; D045792:Norisoprenoids / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D011944:Receptors, Androgen / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D018931:Antineoplastic Agents, Hormonal; D047188:Chalcones; D045792:Norisoprenoids; D011944:Receptors, Androgen