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.
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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DOI：
10.1016/j.steroids.2011.06.002
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发表时间：
2011-11
期刊：
影响因子：
2.7
通讯作者：
Njar VC
中科院分区：
文献类型：
--
作者：
Bruno RD;Vasaitis TS;Gediya LK;Purushottamachar P;Godbole AM;Ates-Alagoz Z;Brodie AM;Njar VC
在我们的临床候选物5（VN/124-1或TOK-001）和类似物作为用于前列腺癌治疗的潜在药剂的继续研究中，合理地设计和合成了化合物5的推定代谢物（10、15和18）。然而，在几项体外研究中，这些药物中没有一种有效。使用蛋白质印迹分析，我们已经产生了一个初步的结构-活性关系（SAR）的5和相关的类似物作为雄激素受体消融剂（ARAAs）。在体内使用雄激素依赖性LAPC-4前列腺癌异种移植模型，我们首次证明了5比目前处于III期临床试验的17-裂解酶抑制剂3（阿比特龙）/4（醋酸阿比特龙）更有效。为了优化5的效力，分别在体内评价了设计用于增加5的稳定性和口服生物利用度的化合物6（3 β-氟-）和9（3β-氨基磺酸酯-）。我们表明，在等摩尔基础上，化合物6对LAPC-4异种移植物的有效性比5高约2倍，但用6观察到的毒性是令人担忧的。这些研究进一步证明了5在临床相关前列腺癌模型中的功效，并证明了其作为前列腺癌潜在治疗的当前临床开发。
In a continuing study of our clinical candidate 5 (VN/124-1 or 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.
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