The optimization of compounds that selectively inhibit protein synthesis for the

选择性抑制蛋白质合成的化合物的优化

• 批准号: 8546999
• 负责人: Cathy A Swindlehurst
• 金额: $ 83.38万
• 依托单位: NOVOMEDIX, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8546999
• 关键词: Animal Model; Biological Availability; Breast Cancer Cell; Breast Cancer Model; Cancer cell line; Cardiac; Cells; Cessation of life; Clinical Trials; Development; Disease; Dose; Drug Formulations; Drug Interactions; Drug effect disorder; ERBB2 gene; Estrogen receptor negative; Eukaryotic Initiation Factor-4E; Goals; Growth; Human; In Vitro; Lead; Legal patent; Malignant Neoplasms; Mammary Neoplasms; Messenger RNA; Molecular Weight; Mus; Normal Cell; Oral; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Prevention; Process; Progesterone Receptors; Property; Protein Biosynthesis; Proteins; Recurrence; Risk; Route; Safety; Schedule; Small Business Innovation Research Grant; Structure; Survival Rate; Therapeutic; TimeLine; Toxic effect; Toxicokinetics; Translation Initiation; Translations; Work; Xenograft Model; cancer cell; clinically relevant; in vivo; inhibitor/antagonist; killings; mRNA capping; malignant breast neoplasm; method development; mouse model; novel; overexpression; preclinical study; programs; public health relevance; safety testing; scale up; small molecule; triple-negative invasive breast carcinoma; tumor

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.

描述(由申请人提供)：该计划的目标是完成适当的临床前研究，以支持IND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，重点是减少复发和提高生存率。与其他形式的乳腺癌不同，三阴性肿瘤没有针对性的治疗方法。不幸的是，三重阴性乳腺癌(TNBC)可能比其他乳腺癌亚型更具侵袭性，更容易复发，导致死亡风险增加。真核细胞的mRNAs有一个独特的5‘端(M7GpppN)，在正常细胞中被严格控制，是启动蛋白质合成所必需的，称为帽依赖翻译。放松对帽子依赖的翻译的管制可能会导致不受控制的生长，这是癌细胞的一个特征。蛋白质合成调控的一个主要靶点是真核生物起始因子4E(EIF4E)，它最为人所知的是在细胞内m7GpppN封顶的mRNAs上启动蛋白质合成的功能。高比例的三阴性乳腺肿瘤有高水平的eIF4E表达，eIF4E水平的升高被证明与更高的复发率和更高的死亡风险相关。由于高水平的eIF4E代表高水平的帽依赖翻译；这项提议的重点是在该提议的第一阶段选择性地抑制蛋白质帽依赖翻译的化合物，NovoMedex在三阴性乳腺癌动物模型中证明了三种新型帽依赖翻译抑制剂的安全性和有效性。已经申请了一项专利，涵盖其中两种化合物(物质组合物专利，用于治疗、预防和/或改善包括癌症在内的各种疾病)，NovoMedex目前正在为第三种化合物申请专利。在这项提案的第二阶段，NovoMedex将首先对这些药物进行额外的体外安全性测试 目的是开发一流的治疗药物，以识别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；以及进行探索性和确凿的临床前研究，以确定支持IND的给药范围、给药途径(口服或静脉注射)和给药时间表，并将其中一种或多种药物推向临床试验。这一阶段的具体目标是 建议：1)评估心脏风险并确定潜在的药物-药物相互作用；2)确定抑制帽依赖翻译启动的机制；3)在三阴性乳腺癌模型中选择安全的给药途径、剂量范围和给药时间表；4)进行分析性表征、配方和GMP放大，以支持GLP临床前研究和I/II期临床试验；5)对两个相关物种进行GLP毒性和毒代动力学研究，以确定用于首例人体I/II临床试验的合适的起始剂量。