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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）：该项目的目标是开发并最终商业化抑制帽依赖性翻译起始的小分子药物，用于治疗三阴性（雌激素受体、孕激素受体和HER 2阴性）乳腺肿瘤，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。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;该提案的重点是选择性抑制蛋白质的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选择性抑制帽依赖性翻译的小分子，并选择了先导化合物用于进一步开发。在I期，将合成另外的化合物，并评价选择性帽依赖性翻译与癌细胞生长抑制之间的相关性，并开发用于癌症生长抑制的结构活性关系。将在原代成纤维细胞、外周血单核细胞和CD 34+细胞上测试这些化合物，以确定对正常细胞的毒性。还将在基于细胞的测定中测试化合物的帽依赖性翻译产物，以帮助阐明作用机制。将以迭代方式进行上述试验中的化合物合成和表征，直至鉴定出先导候选物。铅分子将具有至少微摩尔活性，对非恶性细胞的毒性最小，并且是稳定的，适合于药物开发，并且是新颖的。先导化合物将按比例放大，并进一步表征药代动力学和安全性。体内疗效和其他IND使能临床前研究将在II期进行。由此产生的候选药物将为三阴性乳腺癌提供第一个靶向小分子疗法。该项目的具体目标是：1）通过合成和生物学试验100-150种其他化合物，开发先导化合物的SAR，2）评估体外PK特性，3）放大和表征先导化合物，以及4）确定体内PK和安全性。公共卫生相关性：该计划的目标是开发并最终商业化第一种针对三阴性乳腺癌的靶向治疗，三阴性乳腺癌可能特别具有侵袭性，并且比其他乳腺癌亚型的复发率和死亡率更高。