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美国国立卫生研究院足够的支持这一挑战，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。在过去的八年里，我们已经产生了数据，支持在非常罕见的尤因氏肉瘤中直接靶向理想的癌症靶点。这种理想的癌症靶点源于肿瘤特异性染色体易位，仅存在于肿瘤中，而不存在于正常细胞中。染色体易位导致一种新的融合蛋白EWS-FLI1的合成。这种理想的靶标是一种转录因子，缺乏酶活性，因此通常认为直接靶向是不可能的。我们的方法认识到癌细胞转录是一个高度平衡的过程，需要多种蛋白质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-蛋白相互作用为靶向治疗提供了新的机会。早期的研究发现RNA解旋酶A （RHA）是EWS-FLI1的关键伙伴，最近的一篇论文揭示了RHA对EWS-FLI1的肽和小分子（YK-4-279）破坏导致Ewing肉瘤细胞凋亡。这种RC4机制为直接将这些基础科学发现推进到新的更好的治疗中提供了机会。为了准备这一应用，我们在三个独立的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）合成的先导。该提案的总体目标是优化给药方法并获得毒理学数据，以提交研究性新药（IND）申请，从而进行同类首次，首次人体临床试验。本提案中提出的实验将潜在地刺激药理学开发的一个新领域的开放，即转录的小分子蛋白质-蛋白质相互作用抑制剂（SMPPII）。我们多学科团队的人才使我们能够发现一个成功的小分子，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RC4的资助下，这项工作将得到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资助。该提案包括一项临床试验，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对特定疾病的疗效。未来的增长还将来自于针对依赖异常转录来改善人类健康的其他癌症和其他疾病。

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.