The optimization of compounds that selectively inhibit protein synthesis for the

描述（由申请人提供）：该项目的目标是完成适当的临床前研究，以支持用于三阴性（雌激素受体、孕激素受体和HER2阴性）乳腺癌的一流小分子治疗药物的IND，重点是减少复发和提高生存率。与其他形式的乳腺癌不同，三阴性肿瘤没有靶向治疗方法。不幸的是，三阴性乳腺癌（TNBC）可能特别具有侵袭性，比其他乳腺癌亚型更容易复发，导致死亡风险增加。真核mrna具有独特的帽端5'端（m7GpppN），这是启动蛋白质合成所需的，称为帽依赖翻译，在正常细胞中受到严格控制。对帽依赖翻译的解除管制可能导致不受控制的生长，这是癌细胞的一个标志。蛋白质合成控制的一个主要目标是真核起始因子4E (eIF4E)，其最著名的功能是在细胞中m7GpppN覆盖的mrna上启动蛋白质合成。高比例的三阴性乳腺肿瘤具有高水平的eIF4E表达，并且eIF4E水平升高已被证明与较高的复发率和死亡风险增加相关。因为高水平的eIF4E代表着高的帽依赖翻译率；该提案的重点是选择性抑制蛋白质帽依赖性翻译的化合物。在该提案的I期研究中，NovoMedix在三阴性乳腺癌动物模型中证明了三种新型帽依赖性翻译抑制剂的体内安全性和有效性。其中两种化合物已经申请了专利（用于治疗、预防和/或改善各种疾病（包括癌症）的物质组合专利），NovoMedix目前正在为第三种化合物申请专利。在该提案的第二阶段，NovoMedix将首先对这些药物进行额外的体外安全性测试

DESCRIPTION (provided by applicant): The goal of this program is to complete the appropriate preclinical studies to support an IND for a first-in- class small molecule therapeutic for triple negative (estrogen receptor, progesterone receptor, and HER2 negative) breast cancer with an emphasis on reducing recurrence and increasing survival rates. Unlike other forms of breast cancer, no targeted therapy exists for triple negative tumors. Unfortunately, triple negative breast cancers (TNBC) can be particularly aggressive and more likely to recur than other breast cancer subtypes, resulting in an increased risk of death. Eukaryotic mRNAs possess a unique capped 5'-end (m7GpppN) that is required for initiation of protein synthesis known as cap-dependent translation and in normal cells, is tightly controlled. Deregulation of cap-dependent translation can lead to uncontrolled growth, a hallmark of cancer cells. A prime target of protein synthesis control is the eukaryotic initiation factor 4E (eIF4E), best known for ts function in the initiation of protein synthesis on m7GpppN capped mRNAs in the cell. A high percentage of triple negative breast tumors have high levels of eIF4E expression and elevated levels of eIF4E have been shown to correlate with higher rates of recurrence and increased risk of death. Because high levels of eIF4E represent high rates of cap-dependent translation; the focus of this proposal is on compounds that selectively inhibit cap-dependent translation of proteins In Phase I of this proposal, NovoMedix demonstrated in vivo safety and efficacy of three novel inhibitors of cap-dependent translation in animal models of triple negative breast cancer. A patent has been applied for that covers two of these compounds (composition of matter patent for the treatment, prevention, and/or amelioration of various disorders, including cancer) and NovoMedix is currently working on a patent application for the third compound. In Phase II of this proposal, NovoMedix will perform additional in vitro safety testing on these first in-class therapeutics to identify potential cardiac and hemolytic risks and identify potent drug interactions; to further delineate the mechanism-of-action by which these drugs effectively kill cancer cells in TNBC mouse models; and perform exploratory and definitive preclinical studies to determine dosing range, dosing route (oral or i.v.), and dosing schedule in support of an IND and to advance one or more of these drugs into clinical trials. The specific aims for this Phase II proposal are: 1) to assess cardiac risks and identify potential drug-drug interactions, 2) to identify the mechanism of inhibition of cap-dependent translation initiation, 3) , select a safe an effective route of administration, dosing range, and dosing schedule in a triple negative breast cancer model, 4) conduct analytical characterization, formulation, and GMP scale-up to support GLP preclinical studies and Phase I/II clinical trials, and 5) perform GLP toxicity and toxicokinetic studies in two relevant species to identify an appropriate starting dose for use in first-in-human Phase I/II clinical trials. PUBLIC HEALTH RELEVANCE: The goal of this program is to complete the appropriate preclinical studies to support an IND for a first-in-class small molecule therapeutics for triple negative (estrogen receptor, progesterone receptor, and HER2 negative) breast cancer with an emphasis on reducing recurrence and increasing survival rates.