Small molecule inhibitors of oncogenic miR-21

项目摘要： 公司发展- Ithax Pharmaceuticals是一家新的分拆生物技术公司，位于西雅图， 专注于开发针对癌症和其他慢性疾病中非编码RNA的小药物样分子， 疾病其创始人的经验涵盖药物设计，RNA结构，癌症生物学和生物技术 管理，并包括几个生物技术公司的成功分拆。它给公司一个 在RNA新公司的技术和商业开发方面拥有无与伦比的经验- 肿瘤空间 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的眼中，推进和降低Ithax商业化计划的风险至关重要 伙伴这个项目的完成将有助于公司填补创始人在学术发现方面留下的空白 通过提供在随后的已经计划的药物化学优化下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。 原癌基因非编码RNA miR-21在几乎所有人类肿瘤中过度表达。其 过度表达与多种癌症中不利的患者预后和对 化疗和免疫治疗。在许多细胞和多个小细胞中积累证据 癌症的动物模型表明，miR-21的药理学抑制将阻止癌症的进展。 即使是晚期癌症，它们对这种oncomiR“上瘾”，也会降低化疗耐药性， 检查点免疫疗法 Ithax的第一个先导小分子来自华盛顿大学和 MD安德森癌症中心鉴定新的miRNA生物合成抑制剂。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“Lipinski”药物样分子， 通过直接结合抑制胃癌和胰腺癌细胞的积聚并降低其增殖， to pre-miR-21.本项目将确定抑制的结构、生物化学和细胞机制;以及 在小鼠胃溃疡模型中评价给药安全性、药代动力学、药效学和疗效 癌

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.