Project 2: Developing an N-terminal inhibitor of the androgen receptor

项目总结/摘要 该项目的首要目标是开发一种靶向雄激素受体的先导化合物 (AR)N-末端结构域到早期临床试验，长期目标是将药物纳入监管 批准延长预期寿命并改善转移性去势患者的生活质量 耐药前列腺癌（mCRPC），前列腺癌的阶段和状态，几乎占所有 前列腺癌的死亡率因此，该项目的重点是药物发现和开发。 几年的临床前研究和随后的原理性临床试验证明， AR在CRPC出现中的病理生理作用。不幸的是，主要或次要的阻力， 所有现有的药物都会出现在所有患者身上。因此，存在未满足的临床需求，以开发有效的抗肿瘤药物。 在阿比特龙治疗后/Enzalutamide治疗后环境中可作为单药应用的治疗， 与目前的第二代AR抑制剂组合，以提高 mCRPC患者的生活。 重要的是，AR的C-末端配体结合结构域（LBD）代表了AR的直接或间接结合结构域。 在临床使用中，所有药物作用剂的间接分子靶点。AR的其他主要领域， 包括位于中心的DNA结合结构域（DBD）和N-末端反式激活结构域（NTA）， 还没有被直接靶向并用于治疗益处。由于机管局的主要职能是 转录因子及其遗传效应是去势发展所必需的 因此，我们假设通过干扰AR基因的表达来抑制AR转录活性的方法， 该抑制剂将抑制AR依赖性CRPC细胞的生长。在追求这一假设时，PI已经 在过去的几年里，JN和JN合作鉴定了一系列（“JN”系列）有效的AR抑制剂， 具有以下特点：1）AR β作为分子靶点，2）直接性、选择性、高亲和力和共价性 与AR结合，3）药物诱导的全长AR（ARFL）和组成型活性AR的快速降解 缺乏功能性LBD的剪接变体（ARSV），4）对表达AR的前列腺的选择性细胞减少作用 癌细胞系，包括表达AR β LBD的细胞系，5）CRPC异种移植物的生长抑制，和6） 抑制AR驱动的基因表达。在临床前和临床开发的进展中， JN系列化合物，我们建议阐明JN系列的详细作用机制 并通过进一步的构效关系分析鉴定出先导化合物， 将在IND启用研究中进行临床前验证和测试。在第五年的奖项，我们将启动 我们的先导化合物的首次人体一期研究

Project Summary/Abstract The overarching goal of this project is to bring a lead compound that targets the androgen receptor (AR) N-terminal domain to early phase clinical trials with the long-term goal of bringing a drug to regulatory approval that prolongs life expectancy and improves the quality of life of patients with the metastatic castration resistant prostate cancer (mCRPC), the stage and state of prostate cancer that accounts for virtually all prostate cancer-specific mortality. Thus, the key focus of this project is drug discovery and development. Several years of preclinical studies and subsequent proof-of-principle clinic trials established a pathophysiologic role for the AR in the emergence of CRPC. Unfortunately, primary or secondary resistance to all currently available drugs emerges in all patients. Thus, there is an unmet clinical need to develop effective therapies that can be applied as single agents in the post-abiraterone/post-enzalutamide setting and potentially in combination with current secondary generation AR inhibitory agents to improve the quality and quantity of life of mCRPC patients. Importantly, the C-terminal ligand binding domain (LBD) of the AR represents the direct or indirect molecular target of all hormonally acting agents in clinical use. Other major domains of the AR, including the centrally located DNA binding domain (DBD) and N-terminal transactivation domain (TAD), have yet to be directly targeted and exploited for therapeutic benefit. Given that the AR principally functions as a transcription factor and its genotropic effects are required for the development of castration resistance, we hypothesized that approaches to inhibit AR transcriptional activity by interfering with the TAD will suppress the growth of AR-dependent CRPC cells. In pursuit of this hypothesis, the PIs have collaborated for the last several years to identify a series (the “JN” series) of potent AR inhibitors with the following characteristics: 1) AR TAD as the molecular target, 2) direct, selective, high affinity and covalent binding to the AR, 3) drug-induced rapid degradation of the full-length AR (ARFL) and constitutively active AR splice variants that lack a functional LBD (ARSVs), 4) selective cytoreductive effects on AR expressing prostate cancer cell lines, including AR∆LBD expressing cell lines, 5) growth inhibition of CRPC xenografts, and 6) inhibition of AR-driven gene expression. In the advancement of the pre-clinical and clinical development of JN series compounds, we propose to elucidate the detailed mechanism of action of the JN series compounds and identify a lead compound through further structure activity relationship analysis that will be pre-clinically validated and tested in IND-enabling studies. In year 5 of the award, we will initiate a first-in-human phase 1 study of our lead compound.