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

Creative Commons License

Bruno R. D., Vasaitis T. S., Gediya L. K., Purushottamachar P., Godbole A. M., ALAGÖZ Z., ...Daha Fazla

STEROIDS, cilt.76, sa.12, ss.1268-1279, 2011 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 76 Sayı: 12
  • Basım Tarihi: 2011
  • Doi Numarası: 10.1016/j.steroids.2011.06.002
  • Dergi Adı: STEROIDS
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.1268-1279
  • Anahtar Kelimeler: Androgen receptor, Androgen receptor ablative agents CYP17, CYP17 inhibitors, Prostate cancer therapy, VN/124-1 (TOK-001), Abiraterone, ANDROGEN RECEPTOR, IN-VITRO, POTENTIAL AGENTS, CYP17 INHIBITORS, ANTIANDROGEN, 17-ALPHA-HYDROXYLASE-C-17,C-20-LYASE, P450(17-ALPHA), PROGRESSION, KNOCKDOWN, BLOCKADE
  • Ankara Üniversitesi Adresli: Evet

Özet

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 (3 xi-fluoro-) and 9 (3 beta-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 similar to 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. (C) 2011 Elsevier Inc. All rights reserved.