Combinatorial Approaches for Novel Anticancer Agents

新型抗癌药物的组合方法

• 批准号: 7261878
• 负责人: JOHN S. LAZO
• 金额: $ 125.46万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7261878
• 关键词: Combinatorial; Approaches; Novel; Anticancer; Agents

DESCRIPTION (provided by applicant): The overall goal of this renewal application for a Chemical-Biology Interface Program Project is to generate novel chemical libraries based on potent natural product-derived pharmacophores and to identify promising new lead structures that affect cancer-relevant molecular targets. In this translational application, we intend to exploit recent advances in solid phase and solution phase combinatorial chemistry developed in our laboratories to synthesize unique natural product-based, small-molecular libraries. Our synthetic efforts are focused on two highly relevant molecular targets for solid tumors: (a) microtubules/tubulin, which is an established critical target for several clinically active anticancer agents, including the taxanes and vinca alkaloids, and (b) dual specificity phosphatases that have been documented to be novel proto-oncogenes and regulators of cell cycle progression and apoptosis. In addition to in vitro biochemical assays, we propose to develop and employ novel cellular assays that will be applicable to a wide variety of cancer-related signal transduction and cell structural targets. A highly innovative dynamic combinatorial library approach will also be undertaken to probe new chemical structures and to provide a unique chemical platform for future compound generation. Enhancement and expansion of the fundamental bioisosteres will occur with the assistance of the Bioinformation and Cell-based Assay Core, which will also maintain the central chemical and biological database. Our Preclinical Evaluation Core will evaluate the pharmacodynamics and pharmacokinetics of prioritized compounds in relevant mouse models. Our overall hypothesis is that novel; structurally unique, lead antineoplastic agents can be generated and identified by an integrated use of contemporary combinatorial chemistry, biochemistry, pharmacology, cell biology and informatics.

描述（由申请人提供）：该化学生物学界面计划项目的续订应用程序的总体目标是基于有效的天然产品衍生的药理生成新颖的化学文库，并确定影响癌症相关的分子靶标的有希望的新铅结构。在这种翻译应用中，我们打算利用实验室中开发的固相和溶液相结合化学的最新进展，以综合基于自然产品的独特小分子库。我们的合成努力集中在实体瘤的两个高度相关的分子靶标上：（a）微管/微管蛋白，这是几种临床上活性抗癌药物的既定关键靶标，包括紫杉虫和葡萄球菌生物碱，以及（b）已记录的双重特异性磷酸酶，已记录为新颖的Proto-Proto-Proto-Protos contrest and Aptrestion and cartresty and Crients and contrestress and contrestress and contrestress and condrestress and condrestress and condrestress and condertors and condrestress and confristion。除了体外生化测定外，我们还建议开发和采用新型的细胞测定法，这些测定将适用于多种与癌症相关的信号转导和细胞结构靶标。还将采用高度创新的动态组合图书馆方法来探测新的化学结构，并为将来的复合生成提供独特的化学平台。在生物信息和基于细胞的测定核心的帮助下，基本生物膜蛋白酶的增强和扩展将发生，该核心还将维持中央化学和生物学数据库。我们的临床前评估核心将评估相关小鼠模型中优先化化合物的药效学和药代动力学。我们的总体假设是那个新颖的。可以通过当代组合化学，生物化学，药理学，细胞生物学和信息学的综合使用来生成和识别结构独特的铅抗塑料。