Peptoid conjugates as inhibitors of androgen receptor dimerization and function in enzalutamide-resistant prostate cancer

类肽缀合物作为雄激素受体二聚化抑制剂及其在恩杂鲁胺耐药性前列腺癌中的功能

• 批准号: 9815670
• 负责人: Michael J. Garabedian
• 金额: $ 21.68万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9815670
• 关键词: Address; Affect; Affinity; Androgen Antagonists; Androgen Receptor; Androgen-Insensitivity Syndrome; Androgens; Antiandrogen Therapy; Antitumor Response; Binding; Biological Assay; Cancer Patient; Cancer Vaccines; Cells; Clinic; Clinical; Data; Dimerization; Disease Resistance; Family; Genetic Transcription; Goals; Growth; Homodimerization; Human; In Vitro; Investigation; Lead; Libraries; Life; Ligand Binding; Ligand Binding Domain; Ligands; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Methods; Molecular; Mus; Mutation; N-substituted Glycines; Organ Culture Techniques; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Peptoids; Pharmacology; Pre-Clinical Model; Prostate; Prostate Cancer therapy; Publishing; RNA Interference; Radical Prostatectomy; Receptor Signaling; Refractory; Reporting; Resistance; Testing; Therapeutic; Therapeutic Agents; Transcriptional Activation; Translations; Treatment Protocols; Vertebral column; Xenograft Model; abiraterone; base; castration resistant prostate cancer; chemical synthesis; combat; dimer; gain of function mutation; in vivo; in vivo evaluation; innovation; loss of function mutation; men; novel; novel therapeutics; prostate cancer cell; prostate cancer cell line; prostate cancer model; receptor binding; receptor function; scaffold; targeted agent; therapeutic vaccine; therapy development; therapy resistant; tumor

Project Summary We are pursuing creative efforts to develop therapies urgently needed to treat prostate cancers that become resistant to new anti-androgen therapies. Our approach combines innovations in chemical synthesis with expertise in androgen receptor signaling and prostate cancer. This will allow us to discover a new family of therapeutic agents that combat castration resistant prostate cancer (CRPC) through a unique mode of action that blocks androgen receptor (AR) activity. Indeed, we have developed a new strategy to inhibit the activity of AR by disrupting AR dimerization by displaying AR ligands upon a molecular scaffold. AR dimerization has only been recently recognized as key to determinant to AR activity, and we have developed a novel and facile cell free AR dimerization assay to rapidly test the for effects of the peptoid conjugates on disrupting AR dimerization. We have pioneered an effective method for generating “peptoid” oligomers that incorporate ligands precisely located along the molecular backbone. Our concept is that the conjugates with high affinity ligands for AR will facilitate receptor binding and block AR dimerization more potently and at lower concentrations than low affinity ligands for AR. This has the potential to be exploited to promote an anti-tumor response by targeting AR in a different way than current AR- directed therapies, making this therapeutic strategy conceptually novel and highly innovative. !

项目摘要 我们正在进行创造性的努力，以开发治疗前列腺癌迫切需要的疗法， 对新的抗雄激素疗法产生耐药性。我们的方法结合了化学合成的创新 在雄激素受体信号和前列腺癌方面有专长这将使我们能够发现一个新的家庭， 通过独特的作用模式对抗去势抵抗性前列腺癌（CRPC）的治疗剂 阻断雄激素受体（AR）活性。 事实上，我们已经开发了一种新的策略，通过破坏AR二聚化来抑制AR的活性， 在分子支架上展示AR配体。AR二聚化只是最近才被认为是 我们已经开发了一种新的和简单的无细胞AR二聚化测定， 测试类肽缀合物对破坏AR二聚化的作用。我们开创了一种有效的 产生“类肽”寡聚体的方法，所述寡聚体掺入了精确地沿分子沿着定位的配体， 骨干我们的概念是，具有AR的高亲和力配体的缀合物将促进受体结合， 与AR的低亲和力配体相比，在更低的浓度下更有效地阻断AR二聚化。这具有的 通过以与当前AR不同的方式靶向AR来促进抗肿瘤反应的潜力- 定向疗法，使这种治疗策略在概念上新颖且高度创新。 !