Development of Novel Targeted Therapeutic Agents for Castration Resistant Prostate Cancer

项目总结 这项应用的首要目标是开发一种小分子(S)，它同时针对AR和 用于治疗去势抵抗前列腺癌(CRPC)的表观遗传功能障碍。不受控制的激活 雄激素受体(AR)的表达与前列腺癌(PCa)的发生发展密切相关。 类似地，表观遗传事件通过组蛋白修饰酶，如组蛋白脱乙酰酶介导 (HDAC)，对AR信号的调节是必不可少的。HDAC抑制PCa细胞增殖 通过多种机制，包括AR降解，导致AR信号的抑制。虽然， 目前的AR抑制剂(苯扎鲁胺和阿比特龙)最初是有效的，但这些治疗最终失败 由于AR-Splice Variants(AR-SVS)和AR对雄激素以外的刺激的反应等因素。 全身性HDAC抑制剂(HDACi)，尽管有很好的临床前疗效，但在 慢性前列腺癌患者的临床研究。控制慢性前列腺癌的发生和治疗的有效方法是 开发使用多种机制抑制AR表达或促进AR表达的小分子 退化。如果没有AR，就不会有AR信号，无论是否或多少雄激素 或其他AR信号刺激物存在于CRPC。假设是合理设计的抗雄激素- 配备了增强的生物利用度和效力的HDACi将构成新一代新颖的、有针对性的 抗PCa药物可有效抑制AR和AR-SV早期PCa和CRPC的生长 通过AR的降解直接针对AR。初步研究提供了先导化合物 (抗雄激素-HDACi)与AR进行选择性的肿瘤/组织分布，并有效地抑制AR， HDAC 1和6用于治疗效果。拟议中的研究将解决主流癌症的两个问题 治疗药物-抗雄激素耐药性的发展和HDACI-TO实体瘤疗效的缺乏 提供一类新的靶向药物，具有积极影响CRPC治疗的潜力。具体目标 1)确定具有优化的药代动力学(PK)特性和干净的毒性曲线的抗雄激素-HDACi。 2)探讨细胞内HDAC与AR的作用机制及相互关系 前景看好的抗雄激素药物HDACi的抑制作用。3)确定有希望的治疗效果 抗雄激素-HDACi抑制患者衍生性异种移植和原位种植中CRPC的生长 模特儿口服给药。

PROJECT SUMMARY The overarching goal of this application is to develop a small molecule(s) that targets both the AR and epigenetic dysfunction for the treatment of castration-resistant prostate cancer (CRPC). Uncontrolled activation of androgen receptor (AR) is responsible for the development and progression of prostate cancer (PCa). Similarly, epigenetic events mediated through histone-modifying enzymes, such as histone deacetylases (HDACs), are essential to the regulation of AR signaling. Inhibition of HDACs suppress PCa cell proliferation through multiple mechanisms including AR degradation that results in the inhibition of AR signaling. Although, the current AR inhibitors (enzalutamide and abiraterone) are initially effective, these treatments eventually fail because of factors such as, AR-splice variants (AR-SVs) and AR responding to stimuli other than androgen. Systemic HDAC inhibitors (HDACi), despite promising preclinical efficacy, have shown sub-optimal effects in clinical studies of patients with CRPC. An effective way to control the emergence and treatment of CRPC is to develop small molecules that employ multiple mechanisms to either inhibit AR expression or promote its degradation. If there is no AR, there would be no AR signaling, regardless of whether or how much androgen or other stimuli of AR signaling are present in CRPC. The hypothesis is that rationally designed antiandrogen- equipped HDACi with enhanced bioavailability and potency will constitute a new generation of novel, targeted anti-PCa agents that will effectively inhibit the growth of both AR+ and AR-SV early stage PCa and CRPC by directly targeting AR through its degradation. The preliminary studies have furnished lead compounds (antiandrogen-HDACi) which engage with AR for selective tumor/tissue distribution, and potently inhibit AR, HDACs 1 and 6 for therapeutic impact. The proposed research will solve two problems of main-stream cancer therapy agents – resistance development of antiandrogens and lack of solid tumor efficacy of HDACi – to furnish a novel class of targeted agents with potential to positively impact CRPC treatment. The specific aims are: 1) Identify antiandrogen-HDACi with optimized pharmacokinetic (PK) properties and clean toxicity profile. 2) Investigate the mechanism of action and characterize the correlation between intracellular HDAC and AR inhibition in the promising antiandrogen-HDACi. 3) Determine the therapeutic efficacy of the promising antiandrogen-HDACi to inhibit CRPC growth in patient’s derived xenograft (PDX) and orthotopic implantation models via oral administration.