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: 8726929
• 负责人: Cathy A Swindlehurst
• 金额: $ 33.97万
• 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/8726929
• 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）：该程序的目的是完成适当的临床前研究，以支持第一类小分子疗法的IND，用于三重阴性（雌激素受体，孕酮受体和HER2阴性）乳腺癌，重点是减少复发和增加存活率。与其他形式的乳腺癌不同，没有针对三重阴性肿瘤的靶向疗法。不幸的是，与其他乳腺癌亚型相比，三重阴性乳腺癌（TNBC）可能是特别的侵略性，更可能复发，导致死亡风险增加。真核mRNA具有独特的5'-End（M7GPPPN），这是启动蛋白质合成所必需的称为cap依赖性翻译和正常细胞中所必需的。依赖帽依赖性翻译的放松管制会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4E（EIF4E），它以TS功能在M7GPPPN上蛋白质合成中最著名的M7GPPPN限制了细胞中的mRNA。三重阴性乳腺肿瘤的比例很高，EIF4E表达水平很高，EIF4E的水平升高已显示与更高的复发率和死亡风险增加相关。因为高水平的EIF4E代表了帽依赖性翻译的高速率；该提案的重点是在该提案I期中有选择地抑制蛋白质蛋白质翻译的化合物，Novomedix证明了体内安全性和三种新型帽依赖性翻译抑制剂在三乳腺癌动物模型中的抑制剂。已申请了专利，该专利涵盖了其中两种化合物（包括癌症在内的各种疾病的治疗，预防和/或改善的物质专利组成），而Novomedix目前正在为第三种化合物的专利申请。在该提案的第二阶段中，Novomedix将对这些首次进行额外的体外安全测试 识别潜在的心脏和溶血风险并确定有效的药物相互作用的班级治疗剂；为了进一步描述这些药物在TNBC小鼠模型中有效杀死癌细胞的行动机理；并执行探索性和确定的临床前研究，以确定剂量范围，剂量途径（口服或i.v.）以及支持IND的剂量时间表，并将其中一种或多种药物推向临床试验。该阶段的具体目的 提案是：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cap依赖性翻译启动的机制，3），3），在三重负面乳腺癌模型中选择安全的给药途径，给药范围和给药时间表，4）4）在乳腺癌模型中进行分析和GMP量表，并支持GLP PRETIC和GMP量表，II阶段II/II阶段，II阶段II/II阶段II/II阶段II/II阶段，II阶段II/II阶段，II阶段II/II阶段II/II阶段，II阶段II/II阶段II/II阶段，II/II阶段。在两个相关物种中的有毒动力学研究，以确定适当的起始剂量，以便在人类第一期/II期临床试验中使用。