NEW SMALL MOLECULE INHIBITORS OF MITOSIS

新的有丝分裂小分子抑制剂

• 批准号: 7417957
• 负责人: Timothy J Mitchison
• 金额: $ 49.72万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7417957
• 关键词: ATP phosphohydrolase; Affinity; Antimitotic Agents; Binding; Biochemistry; Biological Assay; Cells; Characteristics; Chemistry; Chromosomes; Complex; Computing Methodologies; Cytology; Dynein ATPase; Family; Funding; Glass; Imides; In Vitro; Informatics; Investments; Kinesin; Label; Libraries; Ligands; Measures; Methods; Microtubules; Mitosis; Mitotic; Mono-S; Motor; Myosin Type II; Numbers; Object Attachment; Paclitaxel; Phenotype; Postdoctoral Fellow; Proteins; Protocols documentation; Quantitative Structure-Activity Relationship; Reagent; Reporting; Research; Research Personnel; Resources; Role; Route; Score; Screening procedure; Slide; Solutions; Specificity; Speed; Steroids; Students; System; Technology; Testing; Time; Tubulin; base; cellular imaging; cycloaddition; depolymerization; drug development; expression cloning; follow-up; improved; in vivo; inhibitor/antagonist; monastrol; novel; polymerization; programs; protein function; scaffold; small molecule; small molecule libraries; tool

In the last funding period we developed a platform to allow post-docs and graduate students to construct libraries of potentially biologically active small molecules in a format that allows efficient screening. In this funding period, we will capitalize on the investment already made by developing libraries based on two approaches in which cycloaddition is followed by specific bond breakage: (1) a macrocyclic scaffold derived from a steroid ring system by sequential cycloaddition and retrocycloaddition; and (2) a library of biaryl macrocycles derived from a cycloaddition/fragmentation strategy. We also plan to perform follow-up chemistry on a number of dihydropyrancarboxamides identified as inhibitors of mitosis during the previous funding period. A second set of technologies developed in the previous funding period allows our library molecules to be arrayed on glass slides and probed with labelled proteins. We plan to exploit these fast, cheap binding assays as a general route to target identification for compounds identified as biologically active in a phenotypic assay.

在上一个资助期间，我们开发了一个平台，允许博士后和研究生以允许有效筛选的格式构建潜在生物活性小分子库。在本次资助期间，我们将利用已经进行的投资，开发基于两种方法的文库，其中环加成后进行特定的键断裂：（1）通过顺序环加成和逆环加成衍生自类固醇环系统的大环支架； (2)源自环加成/断裂策略的联芳基大环化合物库。我们还计划对一些在之前的研究中被鉴定为有丝分裂抑制剂的二氢吡喃甲酰胺进行后续化学研究。 资助期限。上一个资助期开发的第二套技术允许我们的文库分子排列在载玻片上并用标记的蛋白质进行探测。我们计划利用这些快速、廉价的结合测定作为在表型测定中鉴定为具有生物活性的化合物的靶标鉴定的一般途径。