Novel Degraders of the Androgen Receptor (AR) and AR Splice Variants (AR-SVs)

2017年，约有16万男性被诊断出患有前列腺癌，约3万人死于前列腺癌。 在美国，超过330万名男性与PCA一起生存，这一数字预计将增加到450万 到2026年达到100万。目前对晚期去势抵抗前列腺癌(CRPC)的治疗策略包括 雄激素受体(AR)拮抗剂和防止雄激素合成的CYP17A1抑制剂。虽然 这些药物延长了无进展的生存期，大约30%的肿瘤对这些药物没有反应 治疗开始后不久，其余的人就会产生抗药性。其中一个主要原因是 尽管进行了这些治疗，CRPC复发是结构性活性AR剪接变异体(AR-SV)的表达 缺乏配体结合域(LBD)。为了克服这一关键障碍，我们发现了新型的AR拮抗剂 (选择性雄激素受体降解物(SARD))与AR激活功能-1结构域(AF-1)结合 N末端结构域(NTD)和/或LBD拮抗和降解AR和AR-SVS。SARD有独特的 强烈和选择性地拮抗AR并降解全长和剪接的药理特性 多个模型中的AR变量(独立于LBD)。这些SARD抑制前列腺癌细胞的生长，并 依赖AR全长和剪接变体生长的肿瘤。 到目前为止，我们测试的SARD的生物利用度和药物性质都很差。为了克服这些困难 低生物利用度和了解作用机制，我们建议a)开发新的SARD， 将抑制和降解AR的全长和剪接变体，并将被口服生物利用和b)识别 AR及其剪接变异体被降解的机制，导致药物具有更好的疗效。在……下面 AIM-1我们将合成属于新一代SARD的AR拮抗剂，它将降解AR，抑制 前列腺癌的生长，并将口服生物利用度。我们将合成和鉴定口服生物可用SARD 并对体外和体内的PCA和CRPC模型进行评价。这些研究将导致高度有效的 新的SARD将具有类似药物的特性。在AIM-2下，我们将确定泛素化在AR和 通过识别泛素位点并表征其在AR、AR-SV和SARD作用中的作用来降解AR-SV。 AIM-3将致力于确定SARD的清除作用和GATA-2的影响 下调SARD功能。这些研究的预期结果将是新的下一代药物 治疗侵袭性CRPC，研究AR降解的研究工具，更好地了解AR和CRPC 基础生物学，以及将这些分子推向临床的替代终点。

Approximately 160,000 men were diagnosed with prostate cancer (PCa) and around 30,000 died of PCa in 2017. Over 3.3 million men are surviving with PCa in the United States and this number is expected to increase to 4.5 million by 2026. Current therapeutic strategies for advanced castration-resistant prostate cancer (CRPC) include androgen receptor (AR) antagonists and a CYP17A1 inhibitor that prevents synthesis of androgens. Although these drugs extend the progression-free survival, approximately 30% of the tumors do not respond to these therapies and the remaining develops resistance shortly after treatment initiation. One of the primary reasons for CRPC relapse, despite these treatments, is expression of constitutively-active AR splice variants (AR-SV) that lack the ligand binding domain (LBD). To overcome this critical barrier, we discovered novel AR antagonists (Selective Androgen Receptor Degraders (SARDs)) that bind to the AR-activation function-1 domain (AF-1) in the N terminal domain (NTD) and/or LBD and antagonize and degrade AR and AR-SVs. The SARDs have unique pharmacologic properties that strongly and selectively antagonize the AR and degrade full length and splice variant AR (independent of LBD) in multiple models. These SARDs inhibit growth of prostate cancer cells and tumors that are dependent on AR full length and splice variants for growth. The SARDs we have tested thus far have poor bioavailability and drug-like properties. In order to overcome the poor bioavailability and to understand the mechanisms of action, we propose a) to develop novel SARDs that will inhibit and degrade full length and splice variants of the AR and will be orally bioavailable and b) to identify mechanisms by which the AR and its splice variants are degraded, resulting in drugs with better efficacy. Under aim-1 we will synthesize AR antagonists belonging to new generation of SARDs that will degrade the AR, inhibit prostate cancer growth, and will be orally bioavailable. We will synthesize and identify orally bioavailable SARDs and evaluate those using in vitro and in vivo PCa and CRPC models. These studies will result in highly potent new SARDs that will have drug-like properties. Under aim-2, we will identify the role of ubiquitination in AR and AR-SV degradation by discerning ubiquitin sites and characterizing their role in AR, AR-SV, and SARD action. Efforts will be dedicated in aim-3 to determine the scavenging role of SARDs and the implications of GATA-2 down-regulation for SARD function. The expected outcome of these studies will be new next generation drugs to treat aggressive CRPC, research tools to study AR degradation, better understanding of the AR and CRPC basic biology, and surrogate endpoints to advance these molecules to clinic.