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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• 作者：Robert D.  ; Bruno^c ;   ; ¹ ;   ; ³ ; Tadas S.  ; Vasaitis^c ;   ; ² ;   ; ³ ; Lalji K.  ; Gediya^a ;   ; ^c ; Puranik  ; Purushottamachar^a ;   ; ^c ; Abhijit M.  ; Godbole^a ;   ; ^c ; Zeynep  ; Ates-Alagoz^d ;   ; ^e ; Angela M.H.  ; Brodie^c ; Vincent C.O.  ; Njar^a ;   ; ^b ;   ; ^c ;   ; ^{Vincent.njar@jefferson.edu}
• 关键词：Androgen receptor ; Androgen receptor ablative agents CYP17 ; CYP17 inhibitors ; Prostate cancer therapy ; VN/124-1 (TOK-001) ; Abiraterone
• 刊名：Steroids
• 出版年：2011
• 出版时间：November 2011
• 年：2011
• 卷：76
• 期：12
• 页码：1268-1279
• 全文大小：994 K

文摘

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¨Cactivity 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¦Î-fluoro-) and 9 (3¦Â-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 ?-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.