Irreversible Nonsteroidal SARMs for Prostate Cancer

描述（由申请人提供）： 雄激素的生物活性，像其他类固醇一样，通过形成非共价受体-类固醇复合物介导。许多甾体和非甾体抗雄激素，抑制这种复合物的形成，可用于前列腺癌的治疗。然而，所有这些药物都通过可逆的竞争性抑制雄激素与雄激素受体（AR）的结合而起作用。 我们最近报道了不可逆的非甾体抗雄激素和可逆的选择性雄激素受体调节剂（SARM）。这些发现为我们的假设提供了基础，即不可逆SARMs将被证明是治疗前列腺癌的有效和选择性治疗剂。我们建议使用体外实验和小鼠肿瘤异种移植来设计、合成和探索这些药物与前列腺癌细胞系的作用。我们认识到，许多制药公司已经回避开发新的不可逆的AR抑制剂。然而，我们认为，重要的是要广泛探索不可逆AR配体的生物学效应，以确定治疗前列腺癌的最佳方式，并了解配体和受体之间的复杂相互作用。 不可逆的SARM提供了一种独特的药理学工具来做到这一点。我们建议开发新的和新颖的非甾体不可逆SARMs和研究其生物活性，在内源性雄激素的存在下，使用体外和体内模型的组合。我们有目的地避免使用常用的体外共转染模型，因为我们实验室中的证据表明这些模型是体内药理学活性的不良预测因子。我们将结合分子建模、有机合成、药代动力学代谢以及前列腺癌细胞系的体外和体内研究，提供一个综合研究，以了解控制AR抑制前列腺癌生长的无数因素。

DESCRIPTION (provided by applicant): The biological activity of androgens, like other steroids, is mediated through the formation of a noncovalent receptor-steroid complex. A number of steroidal and nonsteroidal antiandrogens, which inhibit formation of this complex, are available for prostate cancer therapy. However, all of these agents act via reversible, competitive inhibition of androgen binding to the androgen receptor (AR). We recently reported on irreversible nonsteroidal antiandrogens and reversible selective androgen receptor modulators (SARMs). These discoveries provide the foundation for our hypothesis that irreversible SARMs will prove to be potent and selective therapeutic agents for the treatment of prostate cancer. We propose to design, synthesize, and explore the actions of these agents with prostate cancer cell lines using in vitro experiments and tumor xenografts in mice. We recognize that a number of pharmaceutical firms have shied away from developing new irreversible inhibitors of the AR. However, we believe that it is important to explore extensively the biological effects of irreversible AR ligands to define the best manner to treat prostate cancer and to understand the complex interaction between ligand and receptor. Irreversible SARMs provide a unique pharmacologic tool to do so. We propose to develop new and novel nonsteroidal irreversible SARMs and study their biological activity using a combination of in vitro and in vivo models in the presence of endogenous androgens. We purposefully avoid the use of commonly employed in vitro cotransfection models due to evidence in our labs demonstrating that these models are poor predictors of in vivo pharmacologic activity. We will use a combination of molecular modeling, organic synthesis, pharmacokinetics metabolism, and in vitro and in vivo studies with prostate cancer cell lines to provide an integrated investigation to understand the myriad factors that govern AR action for inhibition of prostate cancer growth.