Inhibition of the androgen receptor (AR) is the mainstay treatment for advanced prostate cancer. Ralaniten (formally EPI-002) prevents AR transcriptional activity by binding to its N-terminal domain (NTD) which is essential for transcriptional activity. Ralaniten acetate (EPI-506) the triacetate pro-drug of ralaniten, remains the only AR-NTD inhibitor to have entered clinical trials (NCT02606123). While well tolerated, the trial was ultimately terminated due to poor pharmacokinetic properties and resulting pill burden. Here we discovered that ralaniten was glucuronidated which resulted in decreased potency. Long-term treatment of prostate cancer cells with ralaniten results in upregulation of UGT2B enzymes with concomitant loss of potency. This has proven to be a useful model with which to facilitate the development of more potent second-generation AR-NTD inhibitors. Glucuronidated metabolites of ralaniten were also detected in the serum of patients in Phase 1 clinical trials. Therefore, we tested an analogue of ralaniten (EPI-045) which was resistant to glucuronidation and demonstrated superiority to ralaniten in our resistant model. These data support that analogues of ralaniten designed to mitigate glucuronidation may optimize clinical responses to AR-NTD inhibitors.

中文翻译：

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揭示Ralaniten的代谢责任，以增强新型雄激素受体靶向疗法

抑制雄激素受体（AR）是晚期前列腺癌的主要治疗手段。Ralaniten（正式名称为EPI-002）通过结合其转录活性必不可少的N末端结构域（NTD）来阻止AR转录活性。雷拉尼汀的三乙酸酯前药醋酸拉拉汀（EPI-506）仍然是唯一已进入临床试验的AR-NTD抑制剂（NCT02606123）。尽管耐受性良好，但由于药代动力学性能较差并导致药丸负担，该试验最终终止。在这里，我们发现雷拉尼汀被葡糖醛酸糖苷化，导致效力降低。雷拉尼汀对前列腺癌细胞的长期治疗会导致UGT2B酶的上调，并伴有效力丧失。事实证明，这是有助于开发更有效的第二代AR-NTD抑制剂的有用模型。在1期临床试验的患者血清中也检测到了雷拉尼汀的葡萄糖醛酸化代谢产物。因此，我们测试了雷拉尼丁的类似物（EPI-045），该类似物对葡糖醛酸化具有抗性并且在我们的抗性模型中证明了比雷拉尼丁具有优越性。这些数据表明，旨在减轻葡萄糖醛酸化作用的雷拉尼汀类似物可以优化对AR-NTD抑制剂的临床反应。