New type of androgen receptor inhibitors for prostate cancer treatment

描述（由申请方提供）：激素难治性前列腺癌（HRPC）是一种危及生命的疾病，目前可用的药物无法治疗，其中大多数药物靶向雄激素与雄激素受体（AR）的相互作用。虽然肿瘤获得雄激素非依赖性有不同的机制，但所有HRPC肿瘤的一个关键特征是AR保持功能活性，并可能用于保护细胞免于凋亡性细胞死亡。因此，在本建议中，我们探索了一种新的策略，抑制AR作为一种手段，杀死雄激素依赖性和HRPC细胞。这项提案的最终目标是开发一种有效的治疗方法，以对抗目前无法治愈的前列腺癌。在这一目标的驱动下，在我们的初步研究中，我们确定了AR的小分子抑制剂，其作用机制与AR-配体相互作用不同。这些被称为DARNAs的化合物使AR mRNA不稳定，因此从PCa细胞中完全消除AR蛋白。DARNAs在体外和体内均被证明是安全和特异性的抗PCa药物，从而为我们的策略的可行性提供了证据。第一阶段提案的具体目标是：1。围绕两种DARNA化合物的小分子文库的合成用于其药理学优化。我们已经确定了两个DARNA化合物在不同的化学类别。尽管它们在体外表现出特异性和有效地杀死PCa细胞，但它们的药理学特性从未优化过，并且远未达到最佳，包括低代谢稳定性，低溶解度等。在这个特定的目标中，我们将使每个DARNA周围的焦点库敏感。这些化合物库将在第二个具体目标中进行测试，以鉴定具有与DARNA相似的生物学特性和更好的药理学特性的化合物。 2. DARNA化合物的结构活性关系研究，用于鉴定临床前测试和临床开发的最佳AR抑制剂。在第一个特定目的中合成的小分子文库将通过一系列测试，旨在鉴定具有与DARNA相似或更好的针对PCa的特定生物活性和适合于体内测试的药理学性质的化合物。为实现这一目标，可能需要进行几轮合成和测试（构效关系研究）。 在成功完成本阶段研究后，我们计划在项目的第二阶段获得先进的化合物和几种备用化合物，用于临床前试验和新型抗前列腺癌治疗的进一步药物开发。 公共卫生相关性：建议开发抗前列腺癌（PC）的新药。PC是男性人群中最常见的恶性肿瘤，也是最常见的癌症之一。PC的疾病相关死亡率约为12%，但PC的高发病率使得PC相关死亡人数巨大。由于PC对激素治疗的获得性耐药性和对化疗的内在耐药性，PC的治疗选择相当有限。作为这些研究的结果可能开发的新药物具有以下特征：（i）它们将在疾病的所有阶段都是活性的，并且可以在标准雄激素消融治疗失败后主要或作为二线治疗使用，它们可以单独使用或与标准护理组合使用;（ii）它们被认为对抵抗去势、激素戒断、化疗和放疗的PC有活性;（iii）它们特异性靶向表达AR的PC细胞，并且对大多数其他细胞和组织无毒;（iv）与放射和化学疗法相比，它们是安全的，不会引起DNA损伤和继发性癌症。总之，这些新特性将改变前列腺癌治疗领域，并显着降低这种疾病的死亡率和发病率。

DESCRIPTION (provided by applicant): Hormone refractory prostate cancer (HRPC) is a life threatening disease that cannot be treated with currently available drugs, most of which target interaction of androgen with the androgen receptor (AR). While there are different mechanisms by which tumors acquire androgen independence, a key feature of all HRPC tumors is that the AR remains functionally active and likely serves to protect cells from apoptotic cell death. Therefore in this proposal we explore a new strategy for inhibition of AR as a means to kill both androgen dependent and HRPC cells. The ultimate goal of this proposal is to develop an effective therapy against the currently incurable form of prostate cancer. Driven by this goal, in our preliminary studies we identified small molecule inhibitors of AR that act through mechanisms distinct from AR-ligand interaction. These compounds, named DARNAs, destabilize AR mRNA and therefore completely eliminate AR protein from PCa cells. DARNAs were shown to be safe and specific anti-PCa agents in vitro and in vivo, thus providing proof of the feasibility of our strategy. Specific aims of the Phase 1 proposal are: 1. Synthesis of small molecule libraries around two DARNA compounds for their pharmacological optimization. We have identified two DARNA compounds in different chemical classes. Although they demonstrated specific and effective killing of PCa cells in vitro their pharmacological properties were never optimized and are far from optimal, which includes low metabolic stability, low solubility etc. In this specific aim we will sensitize focus libraries around each of DARNAs. These libraries of compounds will be tested in the second specific aim for the identification of compounds with biological properties similar to DARNAs and better pharmacological characteristics. 2. Structure activity relationship studies of DARNA compounds for identification of the best AR inhibitor for pre-clinical testing and clinical development. Libraries of small molecules synthesized in the first specific aim will be passed through a series of tests aimed to identification of compounds with specific biological activity against PCa similar or better than DARNAs and pharmacological properties suitable for in vivo tests. Several rounds of synthesis and testing (structure-activity relationship studies (SAR) may be required to achieve this goal. Upon successful completion of this Phase of the study we plan to have advanced compounds and several back-up compounds for preclinical testing and further drug development of a new type of anti- prostate cancer therapy in Phase II of the project. PUBLIC HEALTH RELEVANCE: Development of new agents against prostate cancer (PC) is proposed. PC is the most frequent malignancy in male population and one of the most frequent cancers in general. Disease-related mortality in PC is around 12%, but very high rate of PC makes number of PC related deaths enormous. Treatment options for PC are rather limited due to acquired resistance of PC to hormonal therapy and intrinsic resistance to chemotherapy. The new agents which may be developed as results of these study have the following features: (i) they will be active on all stages of the disease and may be used primarily or as a second line therapy after failure of standard androgen ablation therapy, they may be used alone or in combination with standard of care; (ii) they supposed to be active against PC resistant to castration, hormone withdrawal, chemo- and radiotherapy; (iii) they are specifically targeted against AR expressing PC cells and non-toxic to most of other cells and tissues; (iv) they are safe and do not cause DNA damage and secondary cancers in contrast to radiation and chemotherapy. Altogether, these new properties would change the field of prostate cancer treatment and significantly decrease mortality and morbidity from this disease.