The optimization of compounds that selectively inhibit protein synthesis for the

描述（由申请人提供）：本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HER 2阴性）乳腺癌的一流小分子治疗药物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。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。真核生物mRNA具有独特的加帽5 '端（m7 GpppN），其是蛋白质合成起始所需的，称为帽依赖性翻译，并且在正常细胞中受到严格控制。帽依赖性翻译的失调可导致不受控制的生长，这是癌细胞的标志。蛋白质合成控制的主要靶标是真核起始因子4 E（eIF 4 E），其在细胞中m7 GpppN加帽的mRNA上的蛋白质合成起始中的功能是众所周知的。高百分比的三阴性乳腺肿瘤具有高水平的eIF 4 E表达，并且已显示升高的eIF 4 E水平与较高的复发率和增加的死亡风险相关。由于高水平的eIF 4 E代表高速率的帽依赖性翻译;本提案的重点是选择性抑制蛋白质帽依赖性翻译的化合物。在本提案的I期研究中，NovoMeidine证明了三种新型帽依赖性翻译抑制剂在三阴性乳腺癌动物模型中的体内安全性和有效性。其中两种化合物已申请专利（用于治疗、预防和/或改善包括癌症在内的各种疾病的物质组合物专利），NovoMeidine目前正在申请第三种化合物的专利。在本提案的第II阶段，NovoMeidine将对这些第一批药物进行额外的体外安全性试验。 确定潜在的心脏和溶血风险并确定有效的药物相互作用;进一步描述这些药物在TNBC小鼠模型中有效杀死癌细胞的作用机制;并进行探索性和确定性临床前研究以确定给药范围、给药途径（口服或静脉内），以及支持IND的给药方案，并将这些药物中的一种或多种推进临床试验。第二阶段的具体目标 建议如下：1）评估心脏风险并确定潜在的药物-药物相互作用，2）确定帽依赖性翻译起始的抑制机制，3）在三阴性乳腺癌模型中选择安全有效的给药途径、给药范围和给药方案，4）进行分析表征、配制和GMP规模扩大以支持GLP临床前研究和I/II期临床试验，和5）在两个相关物种中进行GLP毒性和毒代动力学研究，以确定用于首次人体I/II期临床试验的适当起始剂量。

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.