Novel Antitumor Agents

新型抗肿瘤药物

• 批准号: 8685206
• 负责人: KUO-HSIUNG LEE
• 金额: $ 36.51万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8685206
• 关键词: Antineoplastic Agents; BRCA1 gene; BRCA2 gene; Biological Assay; Biological Factors; Breast Cancer Cell; Breast Cancer Treatment; California; Cancer Etiology; Cancer cell line; Cancer-Predisposing Gene; Cell Cycle Arrest; Cells; Chemicals; Chemotherapy-Oncologic Procedure; Chromatography; Clinical; Clinical Trials; Collaborations; Combinatorial Chemistry Techniques; Couples; Development; Diagnosis; Evaluation; Fractionation; Gene Mutation; 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

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(申请人提供)：拟议研究的目标是从高等植物中发现和开发新类别的抗乳腺癌药物，这些药物过去一直是，现在仍然是新药的重要来源。我们将从稀有歌曲中识别出结构独特的热门歌曲 植物来源，特别是经国家癌症研究所筛选证实具有细胞毒性的热带雨林提取物，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，不仅适用于传统的异种小鼠模型，还适用于具有肿瘤抑制基因BRCA1和P53条件突变的创新和独特的自发性乳腺癌小鼠模型。此外，我们将探索基于化学特征的可能的作用机制(S)以及对相关通路的影响，包括性类固醇受体、细胞周期停滞、激酶抑制或信号转导通路。我们计划的总体目标是确定和开发临床试验候选人，特别是治疗乳腺癌的候选临床试验。为了实现我们的目标，将开展以下具体研究。具体目标-1：体外筛选和生物活性导向的分离和分离，以鉴定乳腺癌选择性化合物，从具有确认活性的植物提取物开始，并根据对乳腺癌细胞株的敏感性进行内部反筛选。具体目标-2：使用合成修饰来改善药理学特征的新的先导化合物优化。新的活性先导化合物(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：分两步进行体内评估，以确认小鼠模型中的活性，包括传统的异种小鼠模型和创新的乳腺癌BRCA1/P53-CREC小鼠模型。特定目标-4：确定乳腺癌治疗的可用药靶点和化合物的作用机制研究。我们计划的优势包括：1)大量的高活性先导化合物和有希望的细胞毒性植物种类，包括来自NCI天然产品储存库计划的热带雨林物种；(2)作为临床试验候选者的具有新作用机制的新先导化合物在分离和结构修饰方面的出色生产力，这反过来又可能导致癌症化疗的创新方法；以及(3)基于新丹参素内酯类似物治疗乳腺癌的良好体内结果，成功开发临床应用药物的前景非常好。我们研究的重点将是从这些不同的化合物类别中寻找最佳的类似物，以便在下一个赠款期间进行抗癌临床试验。