Irreversible Nonsteroidal SARMs for Prostate Cancer

描述(由申请人提供)： 与其他类固醇一样，雄激素的生物活性是通过形成非共价受体-类固醇复合体来调节的。许多类固醇和非类固醇抗雄激素可以抑制这种复合体的形成，可用于前列腺癌的治疗。然而，所有这些药物都是通过可逆的竞争性抑制雄激素与雄激素受体(AR)的结合来发挥作用的。 我们最近报道了不可逆非类固醇抗雄激素和可逆选择性雄激素受体调节剂(SARM)。这些发现为我们的假设奠定了基础，即不可逆转的SARM将被证明是治疗前列腺癌的有效和选择性治疗药物。我们建议设计、合成这些药物，并利用体外实验和小鼠异种肿瘤移植来探索这些药物对前列腺癌细胞株的作用。我们认识到，一些制药公司一直回避开发新的不可逆转的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。 不可逆转的SARM为这样做提供了一种独特的药理学工具。我们建议开发新的和新型的非类固醇不可逆SARM，并在内源性雄激素存在的情况下，使用体外和体内模型相结合的方法研究其生物学活性。我们有意避免使用常用的体外共转染模型，因为我们实验室的证据表明，这些模型对体内药理活性的预测很差。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株的体外和体内研究，提供一项综合研究，以了解影响AR抑制前列腺癌生长的各种因素。

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.