Novel Antitumor Agents

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的抗乳腺癌药物，这些药物一直是并仍然是新药的重要来源。我们将从罕见的 植物来源，特别是B国家癌症研究所筛选证实具有细胞毒活性的雨林提取物，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进行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，而且还使用具有肿瘤抑制基因Brca 1和p53条件突变的创新和独特的遗传工程自发性乳腺癌小鼠模型。此外，我们将根据化学分析和对责任途径的影响来探索可能的作用机制，包括性类固醇受体、细胞周期阻滞、激酶抑制或信号转导途径。我们计划的总体目标是识别和开发临床试验候选人，特别是用于治疗乳腺癌。为实现我们的目标，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级和分离，以确定乳腺癌选择性化合物，从植物提取物开始，具有确认的活性，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：使用合成修饰进行新的电极导线优化，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、物理和光谱技术完成。具体目标3：两步体内评价，以确认在小鼠模型中的活性，包括常规异种移植小鼠模型和创新的乳腺癌Brca 1/p53-Crec小鼠模型。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。我们项目的优势包括：（1）高活性先导化合物和有前途的细胞毒性植物物种的优质供应，包括来自NCI天然产物储存库计划的雨林物种，（2）具有新作用机制的新先导化合物作为临床试验候选物的分离和结构修饰的卓越生产力，这反过来又可能导致癌症化疗的创新方法，和（3）基于新丹参内酯类似物对抗乳腺癌的有希望的体内结果，成功开发临床上有用的药物的上级前景。我们研究的重点将是从这些不同的化合物类别中找到最佳的类似物，以便在下一个资助期内进行抗癌临床试验。

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.