Optimization of compounds that selectively inhibit protein synthesis for the trea

选择性抑制蛋白质合成的化合物的优化用于治疗

基本信息

批准号：
8009311
负责人：
Cathy A Swindlehurst
金额：
$ 30.02万
依托单位：
NOVOMEDIX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8009311
关键词：
Accounting Actins Acute African American Age Animal Model Animals BIRC4 gene Biological Assay Biological Testing Bladder Breast Cancer Cell Breast Cancer Model Breast Cancer Treatment CD34 gene Cancer Etiology Cancer cell line Cell Proliferation Cells Cervical Cessation of life Clinic Colorectal Cyclin D1 Data Death Rate Development Diagnosis Disease Distant Dose Drug Kinetics ERBB2 gene Epidemiologic Studies Estrogen receptor negative Estrogens Ethnic Origin Fibroblasts Goals Growth Head and neck structure Hepatic Hepatotoxicity High Prevalence Human In Situ In Vitro Inhibition of Cancer Cell Growth Inhibitory Concentration 50 Lead Localized Disease Lung Lymphoma MCF7 cell Malignant Neoplasms Malignant neoplasm of prostate Mammalian Cell Mammary Neoplasms Messenger RNA Microsomes Minority Modeling Non-Malignant Normal Cell Peripheral Blood Mononuclear Cell Permeability Pharmaceutical Preparations Phase Plasma Plasma Proteins Polyribosomes Procedures Progesterone Receptors Property Protein Binding Protein Biosynthesis Proteins Race Recurrence Regional Disease Relative (related person)Risk SKBR3 Safety Second Primary Cancers Socioeconomic Factors Stage at Diagnosis Staging Structure-Activity Relationship Survival Rate Synthesis Chemistry Testing Therapeutic Therapeutic Index Toxic effect Toxicity Tests Translation Initiation Translations Woman Work analog animal efficacy base c-myc Genes cancer cell chemotherapy design drug candidate drug development in vivo inhibitor/antagonist lead series liquid chromatography mass spectrometry mRNA capping malignant breast neoplasm novel preclinical study programs public health relevance scale up small molecule triple-negative invasive breast carcinoma tumor

项目摘要

DESCRIPTION (provided by applicant): The goal of this program is to develop and ultimately commercialize small molecule drugs that inhibit cap- dependent translation initiation for the treatment of triple negative (estrogen receptor, progesterone receptor, and HER2 negative) breast tumors 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 can be particularly aggressive and more likely to recur than other breast cancer subtypes, resulting in an increased risk of death. 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. Therefore, previously identified small molecules that selectively inhibit cap-dependent translation were tested in breast cancer models and lead compounds were selected for further development. In phase I, additional compounds will be synthesized and the correlation between selective cap-dependent translation and inhibition of cancer cell growth evaluated and structure activity relationships developed for cancer growth inhibition. These compounds will be tested on primary fibroblasts, peripheral blood mononuclear cells, and CD34+ cells to determine toxicity to normal cells. Compounds will also be tested in cell based assays for products of cap-dependent translation to help elucidate mechanism of action. Compound synthesis and characterization in the above assays will be performed in an iterative manner until lead candidates are identified. Lead molecules will have at least micromolar activity, minimal toxicity to non-malignant cells, and be stable, amenable to drug development, and novel. Lead compounds will be scaled up and further characterized for pharmacokinetic and safety properties. In vivo efficacy and other IND-enabling pre-clinical studies will be performed in phase II. Resulting drug candidates will provide the first targeted small molecule therapy for triple negative breast cancer. The specific aims for this project are: 1) develop SAR of lead compounds through synthesis and biological testing of 100-150 additional compounds, 2) assess in vitro PK properties, 3) scale up and characterize lead compounds, and 4) determine in vivo PK and safety. PUBLIC HEALTH RELEVANCE: The goal of this program is to develop and ultimately commercialize the first targeted therapy for triple negative breast cancer, which can be particularly aggressive and have a higher rate of recurrence and death than other subtypes of breast cancer.

描述（由申请人提供）：该程序的目的是开发并最终将小分子药物商业化，以抑制限制帽的翻译启动，以治疗三重阴性（雌激素受体，孕酮受体和HER2阴性）乳腺癌，并强调减少复发和增加生存率。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，三重阴性乳腺癌可能是特别的侵略性，更有可能复发，导致死亡风险增加。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；该建议的重点是选择性抑制蛋白质帽依赖性翻译的化合物。因此，在乳腺癌模型中测试了先前鉴定的小分子，这些分子选择性地抑制帽依赖性翻译，并选择了铅化合物进行进一步发展。在第一阶段，将合成其他化合物，以及选择性帽依赖性翻译与评估癌细胞生长的抑制与为癌症生长抑制而发展的结构活性关系之间的相关性。这些化合物将在原发性成纤维细胞，外周血单核细胞和CD34+细胞上进行测试，以确定对正常细胞的毒性。化合物还将在基于细胞的cap依赖性翻译产物中测试，以帮助阐明作用机理。上述测定中的复合合成和表征将以迭代方式进行，直到确定铅候选者为止。铅分子至少具有微摩尔活性，对非恶性细胞的毒性最小，并且稳定，适合药物发育和新颖。铅化合物将被缩放并进一步以药代动力学和安全性特性来表征。在II期中，将进行体内疗效和其他指定的临床前研究。最终的候选药物将为三重阴性乳腺癌提供第一个靶向的小分子疗法。该项目的具体目的是：1）通过合成和生物学测试100-150个其他化合物，2）评估体外PK特性，3）扩展并表征铅化合物，并确定体内PK和安全性。公共卫生相关性：该计划的目的是开发并最终将第一种针对性乳腺癌的靶向疗法商业化，这可能是特别具有侵略性，并且比其他乳腺癌的其他亚型具有更高的复发和死亡率。