title: Synthesis and in vitro characterization of ionone-based compounds as dual inhibitors of the androgen receptor and NF-κB.
abstract: Current therapeutic strategy for advanced prostate cancer is to suppress the androgen receptor (AR) signaling. However, lethal castration-resistant prostate cancer (CRPC) arises due to AR reactivation via multiple mechanisms, including mutations in the AR and cross-talk with other pathways such as NF-κB. We have previously identified two ionone-based antiandrogens (SC97 and SC245), which are full antagonists of the wild type and the clinically-relevant T877A, W741C and H874Y mutated ARs. Here, we discovered SC97 and SC245 also inhibit NF-κB. By synthesizing a series of derivatives of these two compounds, we have discovered a novel compound 3b that potently inhibits both AR and NF-κB signalling, including the AR F876L mutant. Compound 3b showed low micromolar antiproliferative activites in C4-2B and 22Rv1 cells, which express mutated ARs and are androgen-independent, as well as DU-145 and PC-3 cells, which exhibit constitutively activated NF-κB signalling. Our studies indicate 3b is effective against the CRPC cells.
authors.affiliation: Segal Cancer Center, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote-Ste-Catherine, Rd., Montreal, QC, H3T 1E2, Canada.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Liu
authors.forename: Jinming
authors.initials: J
authors.lastname: Zhou
authors.forename: Guoyan
authors.initials: G
authors.lastname: Geng
authors.forename: Rongtuan
authors.initials: R
authors.lastname: Lin
authors.forename: Jian Hui
authors.initials: JH
authors.lastname: Wu
mesh_terms: D059002:Androgen Receptor Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D045792:Norisoprenoids / Q000138:chemical synthesis / Q000494:pharmacology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors; D015850:Interleukin-6
chemical_list: D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D016328:NF-kappa B; D045792:Norisoprenoids; D011944:Receptors, Androgen; D000093242:Interleukin-6 Inhibitors; C410798:AR protein, human; C508600:IL6 protein, human; D015850:Interleukin-6