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

描述(由申请人提供)：小分子治疗发展的一个重要障碍是从实验室到临床的转化。最近由美国国立卫生研究院罕见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国家癌症研究所的充分支持，因此需要额外的资助机制。罕见的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的疾病的治疗提供信息。在过去的八年里，我们已经生成了支持在非常罕见的尤因肉瘤中直接靶向理想癌症靶点的数据。这种理想的癌症靶点源于肿瘤特有的染色体易位，这种易位只存在于肿瘤中，而在正常细胞中缺失。染色体易位导致一种新的融合蛋白EWS-FLI1的合成。这个理想的靶点是一个转录因子，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，需要多蛋白复合体来合成和调节mRNA。我们的假设是，EWS-FLI1通过破坏其蛋白质-蛋白质相互作用，为靶向治疗提供了一个新的机会。早期的工作证实RNA解旋酶A(RHA)是EWS-FLI1的关键合作伙伴，最近的一篇文章揭示了来自RHA的EWS-FLI1的多肽和小分子(YK-4-279)中断导致了尤文肉瘤细胞的凋亡。这种RC4机制提供了一个机会，将这些基础科学发现直接推进到新的更好的治疗方法中。在为这一应用做准备的过程中，我们生成了初步数据，在三项独立的毒理学研究中证明了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，作为良好制造规范(GMP)合成的先导。这项提案的总体目标是优化给药方法并获得毒理学数据，以提交一项研究性新药(IND)申请，从而实现一项一流的、第一例人类临床试验。这项提案中提出的实验将潜在地刺激一个新的药理开发领域的打开，即小分子蛋白质-蛋白质相互作用抑制物(SMPPII)的转录。我们多学科团队的人才使我们能够发现成功的小分子，而扩大后的团队包括毒理学家、药理学家和临床试验开发人员。在RC4资助之后，这项工作将通过来自美国国立卫生研究院、慈善机构和小分子开发行业的额外项目赠款来持续进行。这项建议包括一项临床试验，该试验将继续进行未来的第二阶段临床试验，以确定YK-4-279作为一种新型抗癌药物在特定疾病中的疗效。未来的增长还将来自针对更多的癌症和其他依赖异常转录来改善人类健康的疾病。 与公共卫生相关：这项提案的总体目标是优化给药方法并获得毒理学数据，以提交一项研究性新药(IND)申请，从而实现一项一流的、首个人类临床试验。这项提案中提出的实验将潜在地刺激一个新的药理开发领域的打开，即小分子蛋白质-蛋白质相互作用抑制物(SMPPII)的转录。我们多学科团队的人才使我们能够发现成功的小分子，而扩大后的团队包括毒理学家、药理学家和临床试验开发人员。这项建议包括一项临床试验，该试验将继续进行未来的第二阶段临床试验，以确定YK-4-279作为一种新型抗癌药物在特定疾病中的疗效。未来的增长还将来自针对更多的癌症和其他依赖异常转录来改善人类健康的疾病。

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.