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，以支持针对三阴性（雌激素受体、孕激素受体和 HER2 阴性）乳腺癌的首创小分子治疗药物的 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，三阴性肿瘤不存在靶向治疗。不幸的是，三阴性乳腺癌（TNBC）比其他乳腺癌亚型更具侵袭性并且更容易复发，从而导致死亡风险增加。真核 mRNA 具有独特的加帽 5' 端 (m7GpppN)，这是启动蛋白质合成（称为帽依赖性翻译）所需的，并且在正常细胞中受到严格控制。帽子依赖性翻译的失调可能导致不受控制的生长，这是癌细胞的一个标志。蛋白质合成控制的主要目标是真核起始因子 4E (eIF4E)，其最著名的是在细胞中 m7GpppN 加帽 mRNA 上启动蛋白质合成的 ts 功能。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增加的死亡风险相关。因为高水平的 eIF4E 代表高帽依赖性翻译率；该提案的重点是选择性抑制帽依赖性蛋白质翻译的化合物。在该提案的第一阶段，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。已申请涵盖其中两种化合物的专利（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），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 将对这些第一批产品进行额外的体外安全性测试。 一流的治疗方法，以确定潜在的心脏和溶血风险，并确定有效的药物相互作用；进一步阐明这些药物有效杀死 TNBC 小鼠模型中癌细胞的作用机制；进行探索性和明确的临床前研究，以确定剂量范围、给药途径（口服或静脉注射）和给药方案，以支持 IND 并将其中一种或多种药物推进临床试验。第二阶段的具体目标 建议是：1) 评估心脏风险并确定潜在的药物间相互作用，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、剂量范围和给药方案，4) 进行分析表征、制剂和 GMP 放大，以支持 GLP 临床前研究和 I/II 期临床试验，以及 5) 进行 GLP 毒性和 在两个相关物种中进行毒代动力学研究，以确定用于首次人体 I/II 期临床试验的合适起始剂量。