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；然而， 目前的抑制剂往往是复杂的分子，并且存在毒性问题、多药 耐药性、低溶解度和/或缺乏多种癌症功效。总体目标和长期目标 该提案的目的是使用假设驱动的合理药物设计来开发新型杂环 微管蛋白聚合抑制剂。 对本科生使用强大的跨学科指导研究计划 研究人员，我们之前开发了 PY-407-C，一种含有呋喃酮的分子， 阻止微管蛋白聚合并对癌细胞具有纳摩尔毒性。我们的3个独立 但补充目标如下。首先，我们将描述之前确定的 PY (a) 通过分子模型结合微管蛋白的分子，(b) 抑制所需的浓度 与已知抑制剂相比，微管蛋白聚合，以及（c）与非微管蛋白的结合 以便评估特异性。其次，我们将通过合理的药物设计来发现新的药物。 通过假设驱动的多学科合理药物设计循环开发杂环微管蛋白抑制剂 (1) 建模，(2) 我们将从中设计和合成新的基于呋喃酮的目标，以及 (3)测定所得化合物的细胞毒性。生物学结果将推动新的 要建模的合成目标，并且循环将重复。这一目标的创新之处在于 多 PI 提案涉及 2 个不同的本科院校的 3 个实验室的工作 (PUIs) 将汇集不同领域的专业知识来设计微管蛋白抑制剂。此外， 其中许多途径和方法在 PUI 中尤其具有创新性。三、我们要申请 并开发模块化合成方法，以获得设计的抗微管蛋白杂环 通过两种并行的综合策略：（1）应用和扩展我们已发表的工作，同时 (2) 研究利用 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模拟的替代模式 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 使用目标 3 中或通过我们之前发布的合成路线制备的化合物进行。 总体而言，我们将进行基础研究以改进抗癌药物，同时培训下一代 一代科学家。