Purushottamachar Puranik - 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 ...

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      Publication Details (including relevant citation   information):

      Steroids. 2011   Nov;76(12):1268-79. Epub 2011 Jun 24.


      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.

          MID: 21729712    

      Address (URL): http://www.ncbi.nlm.nih.gov/pubmed/21729712