title: Synthesis and biological evaluations of putative metabolically stable analogs of VN/124-1 (TOK-001): head to head anti-tumor efficacy evaluation of VN/124-1 (TOK-001) and abiraterone in LAPC-4 human prostate cancer xenograft model.
abstract: In a continuing study of our clinical candidate 5 VN/124-1 (TOK-001) and analogs as potential agents for prostate cancer therapy, putative metabolites (10, 15 and 18) of compound 5 were rationally designed and synthesized. However, none of these agents were as efficacious as 5 in several in vitro studies. Using western blot analysis, we have generated a preliminary structure-activity relationship (SAR) of 5 and related analogs as androgen receptor ablative agents (ARAAs). In vivo using the androgen-dependent LAPC-4 prostate cancer xenograft model, we demonstrated for the first time that 5 is more efficacious than the 17-lyase inhibitor 3 (abiraterone)/4 (abiraterone acetate) that is currently in phase III clinical trials. In our desire to optimize the potency of 5, compounds 6 (3ξ-fluoro-) and 9 (3β-sulfamate-) designed to increase the stability and oral bioavailability of 5, respectively were evaluated in vivo. We showed, that on equimolar basis, compound 6 was ∼2-fold more efficacious versus LAPC-4 xenografts than 5, but the toxicity observed with 6 is of concern. These studies further demonstrate the efficacy of 5 in a clinically relevant prostate cancer model and justify its current clinical development as a potential treatment of prostate cancer.
authors: Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA.
authors: Robert D
authors: RD
authors: Bruno
authors: Tadas S
authors: TS
authors: Vasaitis
authors: Lalji K
authors: LK
authors: Gediya
authors: Puranik
authors: P
authors: Purushottamachar
authors: Abhijit M
authors: AM
authors: Godbole
authors: Zeynep
authors: Z
authors: Ates-Alagoz
authors: Angela M H
authors: AM
authors: Brodie
authors: Vincent C O
authors: VC
authors: Njar
mesh_terms: D000730:Androstadienes / Q000737:chemistry* / Q000627:therapeutic use*; D000736:Androstenes; D000737:Androstenols / Q000737:chemistry* / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000737:chemistry* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017326:Clinical Trials, Phase III as Topic; D004338:Drug Combinations; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009640:Norethindrone / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011944:Receptors, Androgen / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000031:analogs & derivatives / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000730:Androstadienes; D000736:Androstenes; D000737:Androstenols; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D004338:Drug Combinations; D011944:Receptors, Androgen; C023715:estradiol, norethisterone, testosterone drug combination; D013739:Testosterone; D004958:Estradiol; D013254:Steroid 17-alpha-Hydroxylase; C089740:abiraterone; D009640:Norethindrone; C500627:3-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene