YK-4-279 specifically targets ETS family fusion-protein cancers in clinical trial

YK-4-279在临床试验中专门针对ETS家族融合蛋白癌症

• 批准号: 8047311
• 负责人: JEFFREY A TORETSKY
• 金额: $ 437.47万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2014-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8047311
• 关键词: Address; Advocacy; Animal Model; Antineoplastic Agents; Apoptosis; Area; Basic Science; Binding; Biological; Biological Assay; Biological Availability; Biomedical Research; Canis familiaris; Carcinoma; Cells; Childhood; Chimeric Proteins; Chromosomal translocation; Chronic Myeloid Leukemia; Clinic; Clinical Trials; Clinical Trials Design; Communities; DNA Binding Domain; Data; Development; Disease; Dose; Drug Kinetics; EWS-FLI1 fusion protein; Equilibrium; Ewings sarcoma; FDA approved; Family; Family member; Fund Raising; Funding; Funding Mechanisms; Future; Genetic Transcription; Gleevec; Grant; Growth; Health; Human; Imatinib; Industry; Investigational Drugs; Investigational New Drug Application; Investments; Laboratories; Lead; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Messenger RNA; Methods; Multiprotein Complexes; Mus; Normal Cell; Oral; Pathway interactions; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase II Clinical Trials; Plasma; Preparation; Process; Prostate carcinoma; Protein Family; Protein Tyrosine Kinase; Proteins; Public Health; Publications; RNA helicase A; Rare Diseases; Regulation; Research Infrastructure; Sampling; Talents; Testing; Therapeutic Index; Toxic effect; Toxicology; Transcription Regulatory Protein; Transcriptional Activation; Translating; Translations; United States National Institutes of Health; Work; Xenograft Model; Xenograft procedure; absorption; abstracting; base; bcr-abl Fusion Proteins; bench to bedside; cancer cell; cancer therapy; dosage; good laboratory practice; health care delivery; improved; inhibitor/antagonist; leukemia; multidisciplinary; neoplastic cell; new therapeutic target; novel; novel therapeutics; prevent; protein protein interaction; research and development; research study; response; sarcoma; scale up; small molecule; symposium; therapeutic development; therapeutic target; transcription factor; tumor; tumor growth; young adult

DESCRIPTION (provided by applicant): A significant hindrance of small molecule therapeutic development is translation from the laboratory to the clinic. A recent conference sponsored by the NIH Office of the Director on Rare Diseases recognized the challenge that many rare cancers do not receive adequate support from the NCI, thus additional funding mechanisms are necessary. Rare cancers not only require novel therapy, but many of their unique attributes can inform the therapy of more common diseases. We have generated data over the past eight years supporting direct targeting of an ideal cancer target in the very rare Ewing's Sarcoma. This ideal cancer target originates from a tumor-specific chromosomal translocation only present in the tumor and absent from normal cells. The chromosomal translocation causes the synthesis of a novel fusion protein, EWS-FLI1. This ideal target is a transcription factor and lacks enzymatic activity, thus direct targeting has generally been considered impossible. Our approach recognizes that cancer cell transcription is a highly-balanced process requiring multiprotein complexes for mRNA synthesis and regulation. Our hypothesis was that EWS-FLI1 presents a novel opportunity for targeted therapeutics by means of disrupting its protein-protein interactions. Earlier work identified RNA helicase A (RHA) as a critical partner for EWS-FLI1 and a recent publication revealed peptide and small molecule (YK-4-279) disruption of EWS-FLI1 from RHA caused Ewing's Sarcoma cell apoptosis. This RC4 mechanism provides an opportunity to directly advance these basic science discoveries into new and better treatments. In preparation for this application, we generated preliminary data that demonstrates oral absorption and minimal toxicity from YK-4-279 in three independent toxicology studies. We have also performed scale-up synthesis experiments as a precursor to good manufacturing practice (GMP) synthesis. The overall ambition of this proposal is to optimize delivery methods and obtain toxicologic data for submission of an investigational new drug (IND) application leading to a first-in-class, first-in-human clinical trial. The experiments presented in this proposal will potentially stimulate the opening of a novel area of pharmacologic development, that of small molecule protein-protein interaction inhibitors (SMPPII) for transcription. The talents of our multidisciplinary team enabled us to discover a successful small molecule, while the expanded team includes toxicologists, pharmacologists, and clinical trial developers. Following RC4 funding, this work would be sustainable by additional project grants from the NIH, philanthropy, and industry for small molecule development. This proposal includes a clinical trial that would sustain future phase 2 clinical trials to determine efficacy of YK-4-279 as a novel anti-cancer drug in specific diseases. Future growth will also arise from the targeting of additional cancers and other diseases that rely on aberrant transcription to improve human health. PUBLIC HEALTH RELEVANCE: The overall ambition of this proposal is to optimize delivery methods and obtain toxicologic data for submission of an investigational new drug (IND) application leading to a first-in-class, first-in-human clinical trial. The experiments presented in this proposal will potentially stimulate the opening of a novel area of pharmacologic development, that of small molecule protein-protein interaction inhibitors (SMPPII) for transcription. The talents of our multidisciplinary team enabled us to discover a successful small molecule, while the expanded team includes toxicologists, pharmacologists, and clinical trial developers. This proposal includes a clinical trial that would sustain future phase 2 clinical trials to determine efficacy of YK-4-279 as a novel anti-cancer drug in specific diseases. Future growth will also arise from the targeting of additional cancers and other diseases that rely on aberrant transcription to improve human health.

描述（由申请人提供）：小分子治疗开发的一个重大障碍是从实验室到临床的转化。最近由 NIH 罕见疾病主任办公室主办的一次会议认识到许多罕见癌症没有得到 NCI 足够支持的挑战，因此需要额外的资助机制。罕见癌症不仅需要新的治疗方法，而且它们的许多独特属性可以为更常见疾病的治疗提供信息。我们在过去八年中生成的数据支持直接靶向非常罕见的尤文氏肉瘤中的理想癌症靶点。这种理想的癌症靶点源自仅存在于肿瘤中而正常细胞中不存在的肿瘤特异性染色体易位。染色体易位导致新型融合蛋白 EWS-FLI1 的合成。这种理想的靶标是转录因子，缺乏酶活性，因此直接靶向通常被认为是不可能的。我们的方法认识到癌细胞转录是一个高度平衡的过程，需要多蛋白复合物来合成和调节 mRNA。我们的假设是，EWS-FLI1 通过破坏其蛋白质-蛋白质相互作用为靶向治疗提供了新的机会。早期的工作确定 RNA 解旋酶 A (RHA) 是 EWS-FLI1 的关键伙伴，最近的一篇出版物揭示了 RHA 中 EWS-FLI1 的肽和小分子 (YK-4-279) 破坏导致尤文氏肉瘤细胞凋亡。这种 RC4 机制提供了一个机会，可以将这些基础科学发现直接推进到新的、更好的治疗方法中。为了准备该应用，我们在三项独立毒理学研究中生成了初步数据，证明 YK-4-279 的口服吸收和最小毒性。我们还进行了放大合成实验，作为良好生产规范 (GMP) 合成的前提。该提案的总体目标是优化递送方法并获取毒理学数据，以提交研究性新药 (IND) 申请，从而进行一流、首次人体临床试验。该提案中提出的实验将有可能刺激药理学开发新领域的开放，即用于转录的小分子蛋白质-蛋白质相互作用抑制剂（SMPPII）。我们的多学科团队的才华使我们能够发现一种成功的小分子，而扩大的团队包括毒理学家、药理学家和临床试验开发人员。在获得 RC4 资助后，这项工作将通过 NIH、慈善机构和小分子开发行业的额外项目拨款来维持。该提案包括一项临床试验，该试验将维持未来的 2 期临床试验，以确定 YK-4-279 作为一种新型抗癌药物在特定疾病中的功效。未来的增长还将来自于针对其他癌症和其他依赖异常转录来改善人类健康的疾病。 公共健康相关性：该提案的总体目标是优化给药方法并获取毒理学数据，以提交研究性新药 (IND) 申请，从而进行一流、首次人体临床试验。该提案中提出的实验将有可能刺激药理学开发新领域的开放，即用于转录的小分子蛋白质-蛋白质相互作用抑制剂（SMPPII）。我们的多学科团队的才华使我们能够发现一种成功的小分子，而扩大的团队包括毒理学家、药理学家和临床试验开发人员。该提案包括一项临床试验，该试验将维持未来的 2 期临床试验，以确定 YK-4-279 作为一种新型抗癌药物在特定疾病中的功效。未来的增长还将来自于针对其他癌症和其他依赖异常转录来改善人类健康的疾病。