NPC/MIPE Toxicity Screen of IDH1 Inhibitors against Cholangiocarcinoma Cell Lines

IDH1抑制剂对胆管癌细胞系的NPC/MIPE毒性筛选

• 批准号: 10004990
• 负责人: Matthew Hall
• 金额: $ 25.03万
• 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/10004990
• 关键词: Acute Myelocytic Leukemia; Biliary Tract Cancer; Cell Line; Cholangiocarcinoma; Enzymes; Genetic; Glioma; Goals; Intrahepatic Cholangiocarcinoma; Isocitrate Dehydrogenase; Lesion; Malignant Neoplasms; Metabolic; Mutate; Mutation; Nuclear Pore Complex; Oral; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Property; Survival Rate; Therapeutic; Toxic effect; Unresectable; anti-cancer; carcinogenesis; clinical candidate; improved; inhibitor/antagonist; mutant; pre-clinical; small molecule; small molecule libraries; tumor

This project aims to repurpose approved drugs and other small molecules with well-characterized mechanisms of action for IDH1 anticancer indications by examining toxicity of these small molecules against ICC mutant cell lines. During this period, the project team screened NCGC's small molecule libraries, and identified a number of hit demonstrating selective toxicity against IDH1 mutant cell lines. Focusing on selected candidates, medicinal chemistry optimization has led to improved physiochemical and therapeutic properties, with the ultimate goal of developing an orally available pre-clinical candidate. Advanced characterization of these molecules is underway to further profile their activity and the mechanism of action responsible for the selective lethality in the context of IDH1 mutant ICC cell lines.

该项目旨在通过检测IDH1抗癌小分子对ICC突变细胞系的毒性，将已批准的药物和其他具有良好作用机制的小分子重新用于IDH1抗癌适应症。 在此期间，项目组筛选了NCGC的小分子文库，并确定了一些对IDH1突变细胞系具有选择性毒性的HIT。专注于选定的候选药物，药物化学优化导致了物理化学和治疗性能的改善，最终目标是开发一种口服可用的临床前候选药物。对这些分子的高级表征正在进行中，以进一步描述它们的活性以及在IDH1突变的ICC细胞系中导致选择性致死性的作用机制。