Improving 15-LOX-2 small molecule inhibitors through medicinal chemistry and structure-guided design

通过药物化学和结构引导设计改进 15-LOX-2 小分子抑制剂

• 批准号: 10691131
• 负责人: Alexey Zakharov
• 金额: $ 14.62万
• 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/10691131
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Arachidonate 15-Lipoxygenase; Biological Assay; Cells; Collaborations; Development; Disease; Disease model; Goals; In Vitro; Pharmaceutical Chemistry; Proteins; Research; Research Personnel; Role; Structure; Traumatic Brain Injury; Work; analog; base; design; improved; in vivo Model; inhibitor; protein complex; screening; small molecule; small molecule inhibitor

This project aims to build on previous screening work by developing selective and potent 15-LOX-2 inhibitors, specifically ones capable of disrupting the 15-LOX-2/PEBP1 protein-protein complex and modulate ferroptosis both in in vitro and in vivo models. During this period, the collaborative team initiated the collaboration and outlined a research plan to accomplish the stated project goals. Initial work was also done to design and begin development of potential cell-based assays, and a medicinal chemistry strategies were discussed for the current 15-LOX-2 inhibitor leads. The project team has identified a small molecule that inhibits ferroptosis, and is currently pursuing analogs of the chemotype.

该项目旨在以先前的筛选工作为基础，开发选择性且有效的 15-LOX-2 抑制剂，特别是能够破坏 15-LOX-2/PEBP1 蛋白质-蛋白质复合物并在体外和体内模型中调节铁死亡的抑制剂。在此期间，合作团队发起了合作并制定了研究计划以实现既定的项目目标。还完成了设计和开始开发潜在的基于细胞的测定的初步工作，并讨论了当前 15-LOX-2 抑制剂先导化合物的药物化学策略。该项目团队已经鉴定出一种抑制铁死亡的小分子，目前正在寻找该化学型的类似物。