Discovery and Development of Selective Androgen Receptor Irreversible Covalent Antagonist (SARICA)

选择性雄激素受体不可逆共价拮抗剂（SARICA）的发现和开发

• 批准号: 10302036
• 负责人: Ramesh Narayanan
• 金额: $ 12.68万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10302036
• 关键词: Address; Androgen Antagonists; Androgen Receptor; Applications Grants; Binding; Binding Sites; Biological Assay; CWR22Rv1; Cancer Relapse; Castration; Cell Line; Cell Proliferation; Crystallization; Data; Development; Diagnosis; Diagnostic Reagent; Disease; Dissociation; Drug Kinetics; Failure; Future; Gene Expression; Goals; Growth; Human; Hydrogen Bonding; Hydrophobicity; In Vitro; LNCaP; Lead; Ligand Binding Domain; Liver Microsomes; Malignant neoplasm of prostate; Metabolism; Modeling; Molecular Conformation; Mus; Parents; Pharmacodynamics; Phenotype; Progression-Free Survivals; Property; Prostate; Proteins; RNA Splicing; Rattus; Reagent; Receptor Activation; Receptor Signaling; Refractory; Research; Resistance; Seminal Vesicles; Structure; Structure-Activity Relationship; Tertiary Protein Structure; Testing; Therapeutic; Transactivation; Treatment Failure; United States; Variant; Xenograft procedure; abiraterone; advanced prostate cancer; castration resistant prostate cancer; clinical development; covalent bond; drug development; improved; in vivo; inhibitor/antagonist; men; next generation; novel; novel therapeutics; parent grant; prostate cancer cell; prostate cancer survivors; small molecule; tool; tumor

Approximately 174,000 men in the United States were diagnosed with prostate cancer (PCa) and 31,000 died of PCa in 2019. The number of PCa survivors is expected to increase from 3.3 million men currently to 4.5 million by 2026. One of the primary reasons for treatment failure and castration-resistant prostate cancer (CRPC) relapse is expression of constitutively-active AR splice variants (AR-SVs) that lack the ligand binding domain (LBD) and thus remain constitutively active. AR-SVs contribute to an aggressive phenotype of CRPC, shorter progression-free survival (PFS), and failure to respond to LBD-binding antagonists, enzalutamide or abiraterone. In the parent application, we proposed to discover N-terminus domain (NTD)-binding selective AR degraders (SARDs) as a next-generation treatment for advanced PCa. In the first two years of the parent grant, we serendipitously discovered new set of reagents that bind to the NTD covalently. Our central hypotheses are that the covalently-binding AR inhibitors will serve as the next-generation therapeutics and as a research reagent that will help us to precisely identify the binding site of our SARDs to the AR NTD. To address these hypotheses, we will synthesize covalent molecules that bind strongly and with smaller dissociation constant (kd) for further development for clinical use (specific aims-1 and 2) and use covalent molecules to precisely identify the binding sites of the SARDs and the structure of the AF-1 (specific aim-3). All these studies will help us to increase the impact of the parent grant application, increase the significance of the molecules that are discovered in our parent grant application, and discover new advanced therapeutics. The data will be a harbinger for future development of drugs and diagnostic reagents for the treatment and diagnosis of advanced PCa.

美国约有174，000名男性被诊断患有前列腺癌（PCa），31，000人死于前列腺癌。 2019年的PCa。PCa幸存者的数量预计将从目前的330万男性增加到450万 到2026年治疗失败和去势抵抗性前列腺癌（CRPC）的主要原因之一 复发是缺乏配体结合结构域的组成型活性AR剪接变体（AR-SV）的表达 (LBD)从而保持组成性活性。AR-SV有助于CRPC的侵袭性表型，较短 无进展生存期（PFS），以及对LBD结合拮抗剂恩杂鲁胺或阿比特龙无应答。 在母案申请中，我们提出发现N-末端结构域（NTD）结合的选择性AR降解剂 （SARD）作为晚期PCa的下一代治疗方法。在父母补助金的头两年，我们 偶然发现了一组新的试剂，共价结合到NTD。我们的主要假设是， 共价结合的AR抑制剂将作为下一代治疗药物， 试剂，这将有助于我们精确地确定我们的SARD的结合位点的AR NTD。解决 根据这些假设，我们将合成共价分子， 常数（kd），用于进一步开发临床应用（特定目标-1和2），并使用共价分子 精确鉴定SARD的结合位点和AF-1的结构（特异性目的-3）。所有这些研究 将帮助我们增加父母资助申请的影响，增加分子的重要性， 在我们的母基金申请中被发现，并发现新的先进疗法。数据将是一个 预示着未来发展的药物和诊断试剂的治疗和诊断先进的 PCa。