Novel Antitumor Agents

新型抗肿瘤药物

基本信息

批准号：
8843732
负责人：
KUO-HSIUNG LEE
金额：
$ 37.64万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8843732
关键词：
Antineoplastic Agents BRCA1 gene BRCA2 gene Biological Assay Biological Factors Breast Cancer Cell Breast Cancer Treatment Breast Cancer cell line California Cancer Etiology Cancer-Predisposing Gene Cell Cycle Arrest Cells Chemicals Chemotherapy-Oncologic Procedure Chromatography Clinical Clinical Trials Collaborations Combinatorial Chemistry Techniques Couples DNA Sequence Alteration Development Diagnosis Evaluation Fractionation Genetic Engineering Goals Gonadal Steroid Hormones Grant Housing Human In Vitro Inherited Knockout Mice Laboratory Research Lead Medicinal Plants Methods Modification Molecular Molecular Models Mutation National Cancer Institute Normal tissue morphology Paper Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Phosphotransferases Physical Chemical Technique Plant Extracts Plant Sources Plants Positioning Attribute Predisposition Process Productivity Publishing Receptor Cell Research Risk Signal Transduction Pathway Source Steroid Receptors Structure Structure-Activity Relationship Techniques Therapeutic Uses Treatment-Related Cancer Tumor Cell Line Tumor Suppressor Genes Universities Vascular Plant Woman Xenograft procedure analog antitumor agent base cancer type cytotoxic drug candidate experience improved in vivo innovation malignant breast neoplasm molecular modeling mouse model mutant neotanshinlactone novel pre-clinical preclinical evaluation preclinical study programs public health relevance repository screening

项目摘要

DESCRIPTION (provided by applicant): The objective of the proposed research is to discover and develop new classes of anti-breast cancer agents from higher plants, which have been and still remain a significant source of new drugs. We will identify structurally unique hits from rare sources of plants, particularly rainforest extracts with confirmed cytotoxic activity as screened b the National Cancer Institute, as well as medicinal plants used for cancer-related therapy. Lead compounds, optimized using medicinal chemistry approaches, will be subjected to critical preclinical in vivo assessment, not only with conventional xenograft mouse models, but also with an innovative and unique genetically engineered spontaneous breast cancer mouse model having conditional mutations on tumor suppressor genes Brca1 and p53. Furthermore, we will explore possible mechanism(s) of action based on chemical profiling and effects on responsible pathways, including sex steroid receptors, cell cycle arrest, kinase inhibition, or signal transduction pathways. The overall goals of our program are to identify and develop clinical trial candidates, especially for treating breast cancers. The following specific studies will be carried out to accomplish our goals. Specific Aim-1: In vitro screening and bioactivity-directed fractionation and isolation to identify breast cancer-selective compounds starting from plant extracts with confirmed activity and counter-screened in-house on the basis of susceptibility to breast cancer cell lines. Specific Aim-2: New lead optimization using synthetic modifications to improve pharmacological profile. Structural characterization of new active leads (Aim 1) and modified compounds (Aim 2) will be accomplished by chemical, physical, and spectroscopic techniques. Specific Aim-3: Two-step in vivo evaluations to confirm activity in mouse models, both conventional xenograft mouse models and innovative breast cancer Brca1/p53-Crec mouse model. Specific Aim-4: Mechanism of action studies to identify druggable targets and compounds for breast cancer treatment. Advantages of our program include 1) an excellent supply of highly active lead compounds and promising cytotoxic plant species, including rainforest species from the NCI Natural Product Repository Program, (2) excellent productivity in isolation and structural modification of new leads with new mechanisms of action as clinical trials candidates, which in turn could lead to innovative methods for cancer chemotherapy, and (3) superior prospects for the successful development of a clinically useful drug, based on promising in vivo results with neo-tanshinlactone analogs against breast cancers. An emphasis of our study will be on finding optimal analogs from these different compound classes to advance to anticancer clinical trials during the next grant period.

描述（由申请人提供）：拟议研究的目的是从高等植物中发现和开发新型抗乳腺癌药物，这些植物一直是并且仍然是新药的重要来源。我们将从罕见的结构中识别出结构独特的命中植物来源，特别是经国家癌症研究所筛选具有确认细胞毒性活性的雨林提取物，以及用于癌症相关治疗的药用植物。使用药物化学方法优化的先导化合物将接受关键的临床前体内评估，不仅使用传统的异种移植小鼠模型，还使用创新且独特的基因工程自发性乳腺癌小鼠模型，该模型在肿瘤抑制基因 Brca1 和 Brca1 上有条件突变。第 53 页。此外，我们将根据化学分析和对相关途径的影响，探索可能的作用机制，包括性类固醇受体、细胞周期停滞、激酶抑制或信号转导途径。我们计划的总体目标是确定和开发临床试验候选药物，特别是治疗乳腺癌的候选药物。为了实现我们的目标，将进行以下具体研究。具体目标 1：体外筛选和生物活性导向的分馏和分离，以从具有已证实活性的植物提取物中鉴定乳腺癌选择性化合物，并根据对乳腺癌细胞系的敏感性进行内部反筛选。具体目标 2：使用合成修饰来优化新的先导化合物以改善药理学特征。新活性先导化合物（目标 1）和修饰化合物（目标 2）的结构表征将通过化学、物理和光谱技术来完成。具体目标 3：两步体内评估，以确认小鼠模型（传统异种移植小鼠模型和创新乳腺癌 Brca1/p53-Crec 小鼠模型）中的活性。具体目标 4：作用机制研究，以确定乳腺癌治疗的药物靶点和化合物。我们计划的优势包括 1) 大量供应高活性先导化合物和有前途的细胞毒性植物物种，包括来自 NCI 天然产物存储库计划的雨林物种，(2) 在分离和结构修饰具有新作用机制的新先导化合物方面具有出色的生产力作为临床试验候选者，这反过来可能会导致癌症化疗的创新方法，以及（3）基于新丹参内酯类似物对抗乳腺癌的体内有希望的结果，成功开发临床有用药物的良好前景。我们研究的重点是从这些不同的化合物类别中寻找最佳类似物，以便在下一个资助期内进入抗癌临床试验。