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

在美国，大约有174,000名男性被诊断出患有前列腺癌，31,000人死于 2019年的PCA。预计PCA幸存者的数量将从目前的330万人增加到450万人 到2026年。治疗失败和耐去势前列腺癌(CRPC)的主要原因之一 复发是缺乏配体结合域的结构性活性AR剪接变异体(AR-SVS)的表达 (LBD)，因此在构成上保持活跃。AR-SVS有助于CRPC的侵袭性表型，较短 无进展生存(PFS)，以及对LBD结合拮抗剂苯扎鲁胺或阿比特龙无效。 在父应用程序中，我们提出了发现N-末端结构域(NTD)结合的选择性AR降解物 (SARD)作为晚期PCa的下一代治疗方法。在家长资助的头两年，我们 偶然发现了一组与NTD共价结合的新试剂。我们的中心假设是 共价结合的AR抑制剂将作为下一代治疗药物和研究 试剂，这将帮助我们准确地确定我们的SARD与AR NTD的结合位置。致信地址 在这些假设下，我们将合成结合强烈且解离较小的共价分子。 用于临床进一步开发的常数(Kd)(特定的AIMS-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AIM-3)。所有这些研究 将帮助我们增加父母拨款申请的影响，增加分子的意义 在我们的父母拨款申请中被发现，并发现新的先进疗法。数据将是一个 未来治疗和诊断晚期肺癌的药物和诊断试剂的发展 PCA。

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.