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

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.

VN/124-1 (TOK-001) is more efficacious versus LAPC-4 human prostate cancer tumor xenografts than clinically used abiraterone acetate (zytiga).Figure optionsDownload as PowerPoint slideHighlights
► Synthesis and biological evaluation of putative metabolites and putative metabolically stable analogs of VN/124-1 (5).
► Generated a preliminary structure–activity relationship of 5 and related analogs as androgen receptor ablative agents (ARAAs).
► The 3-fluro analog of 5 (6) was ∼2-fold more efficacious versus LAPC-4 xenografts than 5.
► Demonstrated for the first time that 5 is more efficacious versus LAPC-4 xenografts than abiraterone or its acetate.
► These studies demonstrate the efficacy of 5 in a clinically relevant prostate cancer model.