Development of novel PIP4K inhibitors to treat p53-null cancer

开发新型 PIP4K 抑制剂来治疗 p53 缺失癌症

• 批准号: 10387119
• 负责人: YA HA
• 金额: $ 5.73万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10387119
• 关键词: Animals; Binding; Biological; Biological Assay; Cell Cycle Arrest; Cell Proliferation; Cells; Cellular Metabolic Process; Chemicals; Complex; Crystallization; Development; Distant; Family member; Homeostasis; Hydrophobicity; Hypersensitivity; Insulin; Knock-out; Li-Fraumeni Syndrome; Lipids; Malignant Neoplasms; Molecular Conformation; Muscle Fibers; Mutate; Pharmacology; Phosphorylation; Phosphotransferases; Play; Proliferating; Protein Kinase; Roentgen Rays; Role; Route; Second Messenger Systems; Stress; Structure; TP53 gene; Transgenic Animals; analog; base; cancer cell; design; genetic approach; high throughput screening; human model; inhibitor/antagonist; insulin sensitivity; kinase inhibitor; mouse model; neoplastic cell; novel; small molecule inhibitor; tumorigenesis

PROJECT SUMMARY / ABSTRACT A long-term objective of the project is to develop PI5P4K/ inhibitors as novel pharmacological agents to treat p53-null cancers. PI5P4K and PI5P4K are homologous lipid kinases that play important roles in regulating cell metabolism and proliferation. They catalyze the phosphorylation of PI(5)P to form PI(4,5)P2. Although this is not a major synthetic route for PI(4,5)P2, their activities eliminate PI(5)P, a stress-induced lipid second messenger. Transgenic animals with PI5P4K knocked out are hypersensitive to insulin, and combined knockout with PI5P4K reduce spontaneous tumorigenesis in a mouse model of human Li-Fraumeni syndrome where tumor suppressor p53 is mutated in the germline. In preliminary studies several dihydropteridinone derivatives were identified from high throughput screening as weak inhibitors for PI5P4K. Initial syntheses, guided by X-ray crystallographic analysis of kinase inhibitor complexes, and exploiting a hydrophobic pocket unique to PI5P4K/, have yielded compounds with 50-fold greater potency for both PI5P4K and PI5P4K, and a high degree of selectivity against protein kinases. In specific aim 1, we will continue to modify the most potent inhibitor, based on a co-crystal structure of the compound with PI5P4K, and focusing on a different region of the binding pocket that undergoes conformational change. We plan to solve the crystal structure of the inhibitor with PIKfyve, a distant member of the family, in order to design analogs that do not cross-inhibit it. In specific aim 2, we study how p53(+/+) and p53(-/-) cells respond to the chemical probe. In cultured myotubes, we found that lipid kinase inhibitor disrupted cell energy homeostasis, causing AMPK activation, which may explain enhanced insulin sensitivity observed in animal studies. The possibility that lipid kinase inhibition causes cell cycle arrest by disrupting energy homeostasis in proliferating p53-/- cancer cells will be examined. The synthetic lethal interaction between PI5P4K/ and p53 will be examined by both chemical biological and genetic approaches, and direct engagement of chemical probe with the lipid kinase within proliferating tumor cells will be studied by cellular thermal shift assay (CETSA).

项目摘要/摘要