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

项目摘要/摘要 这个项目的首要目标是带来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，长期目标是将一种药物纳入监管 批准延长转移性去势患者的预期寿命并提高其生活质量 耐药前列腺癌(MCRPC)，前列腺癌的阶段和状态，几乎占所有 前列腺癌特有的死亡率。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则验证临床试验建立了 AR在CRPC发生中的病理生理作用。不幸的是，一次或二次抗性 目前所有可用的药物都出现在所有患者身上。因此，有一种尚未满足的临床需求，即开发有效的药物。 可作为单一药物在后阿比特龙/后苯扎鲁胺环境中应用的治疗方法，并可能 与现有的二代AR抑制药相结合，提高其质量和数量 MCRPC患者的生活。 重要的是，AR的C末端配体结合域(LBD)代表直接或 临床使用的所有激素作用剂的间接分子靶点。AR的其他主要领域， 包括位于中心位置的DNA结合结构域(DBD)和N末端反式激活结构域(TAD)，具有 还没有被直接瞄准并被利用以获得治疗效益。鉴于AR的主要功能是 转录因子及其基因效应在去势发育中的作用 抗药性，我们假设通过干扰抑制AR转录活性的途径 TAD可抑制AR依赖的CRPC细胞的生长。在追求这一假设的过程中，PI已经 过去几年合作确定了一系列(JN系列)有效的AR抑制剂 特点：1)以AR-TAD为分子靶标；2)直接、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)和结构性活性AR的快速降解 缺乏功能性LBD的剪接变异体(ARSVs)，4)对AR表达的前列腺的选择性细胞还原作用 癌细胞系，包括AR∆LBD表达的细胞系，5)对CRPC异种移植的生长抑制，6) 抑制AR驱动的基因表达。在临床前和临床发展方面的进展 对于JN系列化合物，我们建议阐明JN系列化合物的详细作用机理 化合物，并通过进一步的构效关系分析鉴定先导化合物， 将在启用IND的研究中进行临床前验证和测试。在获奖的第五年，我们将发起 这是人类第一次对先导化合物进行第一阶段研究。

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.