Small molecule inhibitors of oncogenic miR-21

项目总结： 公司发展-Ithax PharmPharmticals是一家新的剥离生物技术公司，位于西雅图和 专注于开发针对癌症和其他慢性疾病的非编码RNA的类药物小分子 疾病。其创始人在药物设计、RNA结构、癌症生物学和生物技术方面的经验 管理，包括几家生物技术公司的成功剥离。它给了公司一个 在RNA新公司的技术和商业开发方面拥有无与伦比的经验- 肿瘤学领域。 这项第一阶段的STTR提案列出了一系列实验，超出了学术发现的范围， 在投资者和制药公司眼中，推进和降低Ithax商业化计划的关键 合伙人。这个项目的完成将帮助公司填补创始人在学术发现方面留下的空白 通过提供启动药物化学优化所需的数据 第二阶段SBIR，并成功筹集临床前和临床开发所需的私人资本。 技术--原癌非编码RNA miR-21在几乎每个人类肿瘤中都过度表达。它的 在多种癌症中，过度表达与不良的患者预后有关，并与对 化疗和免疫治疗。在多个细胞和多个小细胞中积累证据 癌症动物模型表明，对miR-21的药理抑制可以阻止肿瘤的进展 即使是对这种肿瘤上瘾的晚期癌症，也会降低化疗耐药性并增强耐药性。 检查点免疫疗法。 Ithax的第一个铅小分子出现在华盛顿大学和 MD Anderson癌症中心，以确定新的miRNA生物发生抑制剂。初步数据显示 ITX-0052是一种具有非常安全的体外药理学特征的利平斯基类药物分子，它抑制miR-21 直接结合低MIC50对胃、胰腺癌细胞的蓄积和抑制增殖作用 到MIR-21之前的版本。该项目将建立抑制的结构、生化和细胞机制；以及 小鼠胃给药安全性、药代动力学、药效学及疗效评价 癌症。

Project Summary: Company development - Ithax Pharmaceuticals is a new spin-off biotechnology company located in Seattle and focused on developing small drug-like molecules that target non-coding RNAs in cancer and other chronic diseases. The experience of its founders’ spans drug design, RNA structure, cancer biology and biotech management, and includes the successful spin offs of several biotech companies. It gives the company an unmatched experience in the technological and commercial development of new companies in the RNA- oncology space. This Phase I STTR proposal lays out a series of experiments, beyond the scope of academic discovery, critical to advance and de-risk the commercialization plans of Ithax in the eyes of investors and pharmaceutical partners. Completion of this project will help the company fill gaps left in the academic discoveries of the founders by providing the data required to initiate medicinal chemistry optimization under a subsequent already planned phase II SBIR, and to successfully raise private capital needed for pre-clinical and clinical development. Technology - The proto-oncogenic non-coding RNA miR-21 is over-expressed in nearly every human tumor. Its over-expression is linked to unfavorable patient prognosis in multiple cancers and resistance to chemotherapeutic and immunotherapeutic treatment. Accumulating evidence in many cellular and multiple small animal models of cancers demonstrates that pharmacological inhibition of miR-21 would stop the progression of even late stage cancers, which are ‘addicted’ to this oncomiR, reduce chemo-resistance and potentiate checkpoint immunotherapy. Ithax’s first lead small molecule emerges from a collaboration between the University of Washington and the MD Anderson Cancer Center to identify new inhibitors of miRNA biogenesis. Preliminary data demonstrate that ITX-0052, a ‘Lipinski’ drug-like molecule with very safe in vitro pharmacological profile, inhibits miR-21 accumulation and reduces proliferation of gastric and pancreatic cancer cells with low M IC50 by binding directly to pre-miR-21. This project will establish the structural, biochemical and cellular mechanism of inhibition; and evaluate safety of administration, pharmacokinetics, pharmacodynamics and efficacy in murine models of gastric cancer.