New type of androgen receptor inhibitors for prostate cancer treatment

用于治疗前列腺癌的新型雄激素受体抑制剂

• 批准号: 7805324
• 负责人: Olga B Chernova
• 金额: $ 10.74万
• 依托单位: TARTIS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7805324
• 关键词: Ablation; Androgen Receptor; Androgens; Antiandrogen Therapy; Apoptotic; Back; Bicalutamide; Binding; Biological; Castration; Cell Death; Cells; Cessation of life; Characteristics; Chemicals; Clinical; DNA Damage; Dependence; Development; Disease; Drug Delivery Systems; Drug resistance; Epithelial Cells; Evaluation; Failure; Future; Gene Amplification; Goals; Hormones; In Vitro; Lead; Libraries; Life; Ligand Binding Domain; Ligands; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Messenger RNA; Metabolic; Morbidity - disease rate; Mutate; Mutation; Names; New Agents; Pathway interactions; Pharmaceutical Preparations; Phase; Population; Preclinical Testing; Probability; Property; Prostate; Prostate Cancer therapy; Prostatic Neoplasms; Radiation; Radiation therapy; Receptor Gene; Receptor Signaling; Resistance; Role; Second Primary Cancers; Series; Solubility; Staging; Structure-Activity Relationship; Testing; Testis; Therapeutic; Tissues; Transactivation; Withdrawal; androgen independent prostate cancer; base; cancer cell; cancer therapy; chemotherapy; drug development; effective therapy; hormone refractory prostate cancer; hormone therapy; human RIPK1 protein; improved; in vivo; inhibitor/antagonist; killings; male; mortality; novel therapeutics; overexpression; phase 1 study; pre-clinical; public health relevance; receptor; receptor function; small molecule; small molecule libraries; standard of care; transcription factor; tumor; tumor progression

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.

描述(申请人提供)：激素难治性前列腺癌(HRPC)是一种威胁生命的疾病，不能用现有的药物治疗，大多数药物针对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的机制不同，但所有HRPC肿瘤的一个关键特征是AR保持功能活跃，可能起到保护细胞免受凋亡细胞死亡的作用。因此，在这项建议中，我们探索了一种抑制AR的新策略，作为一种杀死雄激素依赖和HRPC细胞的手段。这项提议的最终目标是开发一种针对目前无法治愈的前列腺癌的有效疗法。在这一目标的推动下，在我们的初步研究中，我们发现了AR的小分子抑制剂，它们的作用机制与AR-配体相互作用不同。这些化合物被称为DARNAs，它们破坏AR mRNA的稳定，从而完全消除PCa细胞中的AR蛋白。体外和体内实验表明，DARNAs是安全和特异的抗前列腺癌药物，从而证明了我们的策略的可行性。第一阶段方案的具体目标是：1.围绕两个Darna化合物合成小分子文库，用于其药理优化。我们鉴定了两种不同化学类别的达纳化合物。虽然它们在体外显示了对PCa细胞的特异而有效的杀伤作用，但它们的药理作用从未得到优化，而且远未达到最佳，包括低代谢稳定性、低溶解度等。这些化合物文库将在第二个特定目标中进行测试，以鉴定具有类似DARNAs的生物学特性和更好的药理特性的化合物。2.Darna类化合物的构效关系研究，为临床前试验和临床开发寻找最佳的AR抑制剂。在第一个特定目的合成的小分子文库将通过一系列测试，旨在鉴定具有与DARNAs相似或更好的抗PCA特定生物活性的化合物，以及适合体内测试的药理特性。为了实现这一目标，可能需要几轮合成和测试(结构-活性关系研究(SAR))。在这一阶段的研究成功完成后，我们计划在第二阶段的项目中拥有先进的化合物和几种后备化合物，用于临床前测试和进一步开发新型抗前列腺癌疗法。 公共卫生相关性：建议开发抗前列腺癌(PC)的新药物。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的高发病率使得与PC相关的死亡人数巨大。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)它们对疾病的所有阶段都有效，在标准雄激素消融治疗失败后，它们可能主要用于或作为二线治疗，它们可以单独使用或与标准护理结合使用；(Ii)它们被认为对耐去势、激素停用、化疗和放射治疗的PC具有活性；(Iii)它们针对表达AR的PC细胞，对大多数其他细胞和组织无毒；(4)与放射和化疗相比，它们是安全的，不会造成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，并显著降低这种疾病的死亡率和发病率。