Multidisciplinary Investigation of Antitubulin Heterocycles using Synthesis, Biology, and Structural Analysis

利用合成、生物学和结构分析对抗微管蛋白杂环化合物进行多学科研究

• 批准号: 10729604
• 负责人: Kathryn E Cole
• 金额: $ 38.68万
• 依托单位: HOBART AND WILLIAM SMITH COLLEGES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10729604
• 关键词: Acids; American Cancer Society; Antineoplastic Agents; Area; Basic Science; Binding; Biological; Biological Assay; Biological Testing; Biology; Cell Line; Cell Shape; Cell physiology; Cessation of life; Chemistry; Colchicine; Collaborations; Complex; Development; Drug Design; Drug resistance; Future; Generations; Goals; In Vitro; Indoles; Institution; Investigation; Ligand Binding; Ligands; Malignant Neoplasms; Mentors; Methods; Microtubules; Mitosis; Modeling; Multi-Drug Resistance; National Cancer Institute; Organic Chemistry; Organic Synthesis; Pattern; Pharmaceutical Preparations; Polymers; Proteins; Publishing; Research; Research Personnel; Resources; Route; Scientist; Site; Solubility; Specificity; Structure; Structure-Activity Relationship; Study models; Testing; Toxic effect; Training; Tubulin; Work; analog; anti-cancer; cancer cell; cancer therapy; cancer type; combat; cytotoxicity; design; improved; inhibitor; innovation; migration; molecular modeling; multidisciplinary; nanomolar; next generation; novel; novel anticancer drug; organelle movement; polymerization; prevent; programs; rational design; screening; success; therapeutically effective; tubulin polymerization inhibitor; undergraduate student

Tubulin is a protein involved in microtubule function, including mitosis, cell shape, migration, and movement of organelles. Tubulin inhibitors are used in cancer treatments; however, the current inhibitors tend to be complex molecules, and suffer from toxicity issues, multi-drug resistance, low solubility, and/or the lack of multi-cancer efficacy. The overall and long-term goal of this proposal is to use hypothesis-driven rational drug design to develop novel heterocyclic tubulin polymerization inhibitors. Using a robust, interdisciplinary mentoring research program with undergraduate researchers, we previously developed PY-407-C, a furanone-containing molecule that prevented tubulin polymerization and had nanomolar toxicity on cancer cells. Our 3 independent but complementary goals are as follows. First, we will characterize previously identified PY molecules for (a) tubulin binding by molecular modeling, (b) concentration needed to inhibit tubulin polymerization compared to known inhibitors, and (c) binding to non-tubulin proteins in order to assess specificity. Second, we will employ rational drug design to identify new heterocyclic tubulin inhibitors via a hypothesis-driven, multi-disciplinary rational drug design loop of (1) modeling, (2) from which we will design and synthesize new furanone-based targets, and (3) assay the resultant compounds for cytotoxicity. Biological results will then drive new synthetic targets to be modeled, and the loop will be repeated. This aim is innovative in that a multi-PI proposal involving the work of 3 labs at 2 different primarily undergraduate institutions (PUIs) will bring together different areas of expertise to tubulin inhibitor design. Furthermore, many of these approaches and methods are particularly innovative at a PUI. Third, we will apply and develop modular synthetic methods that give access to designed anti-tubulin heterocycles through two parallel synthetic strategies by: (1) applying and extending our published work while (2) investigating innovative strategies that employ C-H activation, thus significantly improving resource efficiency and potentially extending the substitution patterns available for analogue synthesis (including NH indole derivatives). Of note, all aims are independent as aim 2 can be performed with compounds made in aim 3 or by our previously published synthetic routes. Overall, we will perform basic research to improve anticancer agents while training the next generation of scientists.

微管蛋白是一种参与微管功能的蛋白质，包括有丝分裂，细胞形状，迁移， 和细胞器的运动。微管蛋白抑制剂用于癌症治疗；但是， 当前的抑制剂往往是复杂的分子，并且患有毒性问题，多药 抗性，低溶解度和/或缺乏多癌功效。总体和长期目标 该建议的是使用假设驱动的有理药物设计来开发新型的杂环 微管蛋白聚合抑制剂。 使用本科生使用强大的跨学科指导研究计划 研究人员，我们以前开发了PY-407-C，这是一种含呋喃酮的分子 预防小管蛋白聚合，并对癌细胞具有纳莫尔毒性。我们的3个独立 但是互补的目标如下。首先，我们将表征先前确定的PY （a）通过分子建模的微管蛋白结合的分子，（b）抑制所需的浓度 与已知抑制剂相比，微管蛋白聚合和（c）与非微管蛋白蛋白的结合 为了评估特异性。第二，我们将采用合理的药物设计来确定新的 通过假设驱动的多学科有理药物设计环的杂环微管蛋白抑制剂 （1）建模，（2）我们将设计和合成新的基于Furanone的目标，并且 （3）测定所得化合物的细胞毒性。然后生物学结果将推动新 要建模的合成目标，并将重复循环。这个目标是创新的 涉及2个不同的3个不同本科机构的3个实验室工作的多PI提案 （PUI）将把不同的专业知识汇集到微管蛋白抑制剂设计。此外， 这些方法和方法中的许多在PUI中尤其具有创新性。第三，我们将申请 并开发模块化合成方法，可访问设计的抗微管蛋白异环 通过两种平行的合成策略通过：（1）应用和扩展我们已发表的工作 （2）调查采用C-H激活的创新策略，从而显着改善 资源效率，并有可能扩展可用于类似的替代模式 合成（包括NH吲哚衍生物）。值得注意的是，所有目标都是独立的，因为目标2可以是 用在AIM 3或我们先前发表的合成路线中制成的化合物进行的。 总体而言，我们将进行基础研究以改善抗癌剂，同时训练下一项 一代科学家。