Irreversible Nonsteroidal SARMs for Prostate Cancer

不可逆非甾体 SARM 治疗前列腺癌

• 批准号: 6902593
• 负责人: DUANE D MILLER
• 金额: $ 28.17万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6902593
• 关键词: androgen receptor; androgens; cell line; chemical models; chemical synthesis; cytotoxicity; drug design /synthesis /production; drug screening /evaluation; isothiocyanates; laboratory mouse; ligands; molecular dynamics; neoplasm /cancer pharmacology; pharmacokinetics; prostate neoplasms; receptor binding; xenotransplantation

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.

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非共价受体-类固醇复合物的形成来介导的。许多类固醇和非类固醇抗雄激素可抑制这种复合物的形成，可用于前列腺癌治疗。然而，所有这些药物都是通过可逆、竞争性抑制雄激素与雄激素受体 (AR) 的结合来发挥作用。 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奠定了基础，即不可逆 SARM 将被证明是治疗前列腺癌的有效且选择性的治疗剂。我们建议使用体外实验和小鼠肿瘤异种移植物来设计、合成和探索这些药物对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 AR 抑制剂。然而，我们认为，广泛探索不可逆 AR 配体的生物学效应对于确定治疗前列腺癌的最佳方式并了解配体和受体之间复杂的相互作用非常重要。 不可逆 SARM 提供了一种独特的药理学工具来实现这一目标。我们建议开发新型非甾体不可逆 SARM，并在内源性雄激素存在下结合体外和体内模型研究其生物活性。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不能很好地预测体内药理活性。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来提供综合研究，以了解控制 AR 作用以抑制前列腺癌生长的多种因素。