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.

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TitleSynthesis 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.
Publication TypeJournal Article
Year of Publication2011
AuthorsBruno, RD, Vasaitis, TS, Gediya, LK, Purushottamachar, P, Godbole, AM, Ates-Alagoz, Z, Brodie, AMH, Njar, VCO
JournalSteroids
Volume76
Issue12
Pagination1268-79
Date Published2011 Nov
ISSN1878-5867
KeywordsAndrostadienes, Androstenols, Animals, Antineoplastic Agents, Benzimidazoles, Cell Line, Tumor, Cell Proliferation, Clinical Trials, Phase III as Topic, Drug Combinations, Estradiol, Humans, Male, Mice, Mice, SCID, Norethindrone, Prostatic Neoplasms, Receptors, Androgen, Steroid 17-alpha-Hydroxylase, Structure-Activity Relationship, Testosterone, Xenograft Model Antitumor Assays
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.

DOI10.1016/j.steroids.2011.06.002
Alternate JournalSteroids
PubMed ID21729712
PubMed Central IDPMC3171567
Grant ListR01 CA027440-28 / CA / NCI NIH HHS / United States
R01 CA027440-28 / CA / NCI NIH HHS / United States
R21 CA11799-01 / CA / NCI NIH HHS / United States
R21 CA117991-02 / CA / NCI NIH HHS / United States
T32 AG000219 / AG / NIA NIH HHS / United States
T32 ES007263-16A / ES / NIEHS NIH HHS / United States