Small-molecule therapy for metastatic castration-resistant prostate cancer

转移性去势抵抗性前列腺癌的小分子治疗

• 批准号: 10325729
• 负责人: DAQING WU
• 金额: $ 100.78万
• 依托单位: METCURE THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10325729
• 关键词: Affect; Animals; Antineoplastic Agents; Apoptosis; Biological Assay; Bone Tissue; Businesses; Cancer Patient; Cancer cell line; Canis familiaris; Cardiovascular system; Cell Line; Cells; Clinical Pharmacology; Clinical Trials; Collaborations; Complex; Cyclin D1; Developmental Therapeutics Program; Disseminated Malignant Neoplasm; Dose; Drug Kinetics; EZH2 gene; Evolution; Excretory function; Exhibits; F-Box Proteins; Formulation; Future; Generations; Genetic; Grant; Growth; Human; In Vitro; Intervention; Investigational Drugs; Investigational New Drug Application; Lead; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Spectrum Analysis; Medical; Metabolism; Metastatic Neoplasm to the Bone; Modality; Modeling; Molecular Target; Morbidity - disease rate; National Cancer Institute; Oncogenic; Oncology; Oral; Organ; Outcome; Patient Selection; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phosphotransferases; Pilot Projects; Pre-Clinical Model; Prognosis; Property; Proteins; Proteome; Quality of life; Relapse; Rodent; Rodent Model; Role; S Phase; Safety; Sampling; Schedule; Signal Transduction; Solid; Technology Transfer; Testing; Therapeutic; Tissues; Toxic effect; Toxicokinetics; Toxicology; Treatment Efficacy; United States; Ursidae Family; Xenograft Model; Xenograft procedure; abiraterone; absorption; androgen deprivation therapy; base; beta catenin; c-myc Genes; cancer cell; castration resistant prostate cancer; chemotherapy; clinical development; clinically relevant; cytotoxicity; docetaxel; dosage; drug candidate; drug development; efficacious treatment; efficacy study; follow-up; good laboratory practice; improved; in vivo; inhibitor/antagonist; innovation; mortality; nanomolar; new therapeutic target; novel; patient derived xenograft model; pre-clinical; preclinical development; preclinical safety; preclinical study; preclinical toxicity; predictive marker; prostate cancer cell; respiratory; skeletal; small molecule; small molecule inhibitor; subcutaneous; survivin; survivorship; targeted treatment; therapeutic target; therapy resistant; trial design; tumor; tumor progression; ubiquitin ligase

Metastatic, castration-resistant prostate cancer (mCRPC) is lethal with no cure. Although current treatments initially prolong survival, patients generally relapse and develop therapeutic resistance, which is a major obstacle in the management of prostate cancer. It is imperative to develop efficacious therapies to treat lethal mCRPC and improve the survivorship of patients. During the Phase I STTR period, we identified a novel small- molecule inhibitor of S phase kinase-associated protein 1 (Skp1) – F-Box protein (FBP) interaction, namely GH501, that exhibits nanomolar potency against mCRPC and a broad spectrum of human cancer cell lines. We have conducted pilot studies on the preclinical safety, pharmacokinetics, distribution and efficacy of GH501 against mCRPC. In this Phase II STTR project, we will test the central hypothesis that our lead compound GH501 is a first-in-class Skp1-FBP inhibitor that effectively treats mCRPC. The proposed studies are built upon: (1) an urgent and unmet medical need to develop new interventions for lethal mCRPC, (2) an imperative need to identify new therapeutic targets in mCRPC; and (3) strong preclinical evidence supporting GH501 as a novel and effective inhibitor of mCRPC. The overall objective is to conduct Investigational New Drug (IND)- enabling toxicology and efficacy studies on GH501 as a drug candidate for the treatment of lethal mCRPC. In Aim 1, we will develop an oral formulation of GH501 and test the hypothesis that GH501 has excellent safety and drug-like properties in preclinical models. In Aim 2, we will validate the mechanism of action of GH501 and test the hypothesis that as a novel Skp1 inhibitor, GH501 is efficacious against mCRPC in clinically-relevant xenograft models. Completion of the proposed project and follow-up preclinical studies will allow us to prepare an IND application within the next 3~4 years to advance GH501 into human trials. This highly innovative, translational project could have a significant impact in reducing prostate cancer mortality and morbidity.

转移性去势抵抗性前列腺癌（mCRPC）是致命的，无法治愈。虽然目前的治疗 最初延长生存期，患者通常复发并产生治疗抗性，这是主要的 前列腺癌的早期症状有哪些？当务之急是开发有效的治疗方法来治疗致命的 mCRPC，提高患者的生存率。在第一阶段STTR期间，我们发现了一种新的小- S期激酶相关蛋白1（Skp 1）- F-Box蛋白（FBP）相互作用的分子抑制剂，即 GH501，其表现出针对mCRPC和广谱人癌细胞系的纳摩尔效力。 我们对GH501的临床前安全性、药代动力学、分布和疗效进行了初步研究 针对mCRPC。在这个第二阶段的STTR项目中，我们将测试我们的先导化合物 GH501是一流的Skp 1-FBP抑制剂，可有效治疗mCRPC。拟议的研究是建立在 基于：（1）开发致死性mCRPC新干预措施的紧迫且未满足的医疗需求，（2）当务之急 需要在mCRPC中确定新的治疗靶点;（3）强有力的临床前证据支持GH501作为 新型有效的mCRPC抑制剂。总体目标是进行新药临床试验（IND）- 使GH501作为治疗致死性mCRPC的候选药物的毒理学和功效研究成为可能。在 目的1：研制GH501口服制剂，验证GH501的安全性 和临床前模型中的药物样性质。在目标2中，我们将验证GH501的作用机制， 检验以下假设：作为一种新型Skp 1抑制剂，GH 501在临床相关疾病中对mCRPC有效 异种移植模型。完成拟议项目和后续临床前研究将使我们能够准备 在未来3~4年内提交IND申请，推进GH501进入人体试验。这个高度创新的， 翻译项目可能对降低前列腺癌死亡率和发病率产生重大影响。