Identification of Inhibitors of human Galactokinase (GALK) for the treatment of Galactosemia

用于治疗半乳糖血症的人半乳糖激酶 (GALK) 抑制剂的鉴定

• 批准号: 10690363
• 负责人: Min Shen
• 金额: $ 42.54万
• 依托单位: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
• 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/10690363
• 关键词: Animal Model; Biological Assay; Cells; Cessation of life; Chemicals; Classical galactosemia; Development; Disease; Drug Design; Enzymes; Galactose; Galactosemias; Galectin 1; Human; Lead; Left; Measurement; Metabolic; Metabolic Diseases; Paper; Pathogenicity; Patients; Pharmaceutical Chemistry; Publishing; Series; Structure; Symptoms; base; dietary; galactokinase; improved; inhibitor; interest; lead series; liquid chromatography mass spectrometry; novel therapeutics

This project aims to identify and develop inhibitors of GALK as a potential novel therapy for Classic Galactosemia. During this period, the collaborative team continued with its ongoing medicinal chemistry campaign to (1) improve GALK inhibitory activity on the lead series, (2) improve GALK inhibitory activity on the backup series, (2) improve BBB exposure. Compounds of interest have been advanced into cell-based assays and animal models to further characterize their cellular activity. In addition, a cell-based Gal1-p LC/MS assay has been in development to enable direct measurement of the metabolite in cells and provide a much needed marker of on-target activity. A medchem paper was published showcasing structure-based drug design to improve the potency of a the lead chemical series.

该项目旨在识别和开发Galk的抑制剂，作为经典半乳糖血症的潜在新疗法。在此期间，协作团队继续开展其正在进行的药物化学运动，以（1）改善铅系列中的Galk抑制作用，（2）改善备用系列中的GALK抑制作用，（2）改善BBB的暴露。感兴趣的化合物已进入基于细胞的测定和动物模型中，以进一步表征其细胞活性。此外，基于细胞的GAL1-P LC/MS分析已在开发中，以直接测量细胞中的代谢产物，并提供急需的靶向活性标记。 Medchem论文发表了基于结构的药物设计，以提高铅化学系列的效力。