Development of phosphorylation-inducing chimeric small molecules

磷酸化诱导嵌合小分子的开发

• 批准号: 10242051
• 负责人: Amit Choudhary
• 金额: $ 20万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-19 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242051
• 关键词: 5' -AMP-activated protein kinase; Adaptor Signaling Protein; Affinity; Agammaglobulinaemia tyrosine kinase; Attenuated; Binding; Biochemical; Biological; Breathing; Bromodomain; Cells; Chemicals; Complex; Computer Models; Dependence; Development; Dimerization; Dose; Enzymes; Equilibrium; Evaluation; Event; Exhibits; Exploratory/Developmental Grant; Future; HLA Antigens; Immune response; Immune system; Length; Ligands; Mediating; Membrane; Methods; Nature; Nuclear; Pharmaceutical Preparations; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Protac; Protein Isoforms; Protein Kinase; Protein Kinase C; Protein Tyrosine Kinase; Protein-Serine-Threonine Kinases; Proteins; Proteomics; Research; Role; Serine/Threonine Phosphorylation; Signal Transduction; Specificity; Structure; Tacrolimus Binding Protein 1A; Therapeutic; Tyrosine Phosphorylation; computer studies; experimental study; immunoregulation; interest; loss of function; multidisciplinary; neoantigens; phosphoproteomics; programs; protein function; small molecule

PROJECT SUMMARY Protein phosphorylation can activate, inhibit, or modify protein’s function. Small molecules that block protein phosphorylation via kinase inhibition exist, but methods to induce phosphorylation of any protein on demand do not exist. We propose to develop a new class of small molecules, termed PHosphorylation Inducing Chimeric Small molecules (PHICS), which will induce protein phosphorylation with dose and temporal control. PHICS will be formed by joining a small-molecule kinase binder with a small-molecule binder of the target protein so that an active kinase is brought into proximity to the target protein to initiate phosphorylation. 1

项目摘要 蛋白质磷酸化可以激活，抑制或修饰蛋白质的功能。 存在通过激酶抑制的磷酸化，但是诱导任何蛋白质磷酸化的方法 我们不存在。 小分子（PHICS），它将通过剂量和时间对照诱导蛋白质磷酸化 将通过与目标的小分子粘合剂一起连接一个小分子激酶粘合剂来形成 活性激酶与靶蛋白接近以启动磷酸化。 1

项目成果

Synthetic Reprogramming of Kinases Expands Cellular Activities of Proteins.

• DOI: 10.1002/anie.202202770
• 发表时间: 2022-07-18
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Shoba, Veronika M.;Godage, Dhanushka N. P. Munkanatta;Chaudhary, Santosh K.;Deb, Arghya;Siriwardena, Sachini U.;Choudhary, Amit
• 通讯作者: Choudhary, Amit