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Split-luciferase Epigenetic Assays for Drug Discovery

用于药物发现的分裂荧光素酶表观遗传学分析

基本信息

批准号：
10482555
负责人：
REENA ZUTSHI
金额：
$ 24.04万
依托单位：
LUCEOME BIOTECHNOLOGIES, LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10482555
关键词：
Academia Address Architecture Binding Biological Assay Biology Brain Diseases Bromodomain Cells Chemicals Chromatin Clinical Trials Complex Coupled DNA DNA Modification Process Data Deacetylase Development Dihydrofolate Reductase Dimerization Dose EZH2 gene Environment Enzymes Epigenetic Process Escherichia coli Gene Expression Regulation Generations Genetic Transcription Histone Deacetylase Histone-Lysine N-Methyltransferase Histones Human Genome Hybrids Industry Inflammatory Lead Luciferases Lysine Malignant Neoplasms Malignant neoplasm of brain Measurement Mediating Methylation Methyltransferase Modification Nature Nucleosomes Pathway interactions Patients Permeability Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Phenotype Phosphotransferases Post-Translational Protein Processing Process Proteins Reader Regulation Reporting Research Personnel Scaffolding Protein Signal Transduction Site System Tail Technology Tertiary Protein Structure Toxic effect Transcriptional Activation Transferase Validation Writing assay development base candidate identification chemical addition cost design drug discovery effective therapy epigenome feasibility testing gene repression histone acetyltransferase histone methyltransferase histone modification in vitro Assay inhibitor innovation interest lead candidate luminescence nervous system disorder novel therapeutics response success therapeutic candidate wound

项目摘要

Project Summary Epigenetic control is essential for maintaining transcriptional integrity. Regulation of the dynamic epigenome is mediated through a range of post translational modifications on DNA and histone tails. Histone modifications are mediated by enzymes which can be broadly classified into “writers” that catalyze the addition of chemical modifications, “erasers” that remove the modifications, and “readers” that can recognize chemical modifications through specific protein domains. The writing and erasing of histone marks by enzymes is a dynamic process, and when dysregulated is associated with cancer, inflammatory and neurological diseases. In this application we focus on the two classes of histone modifying enzymes, lysine methyl transferases (KMTs) and lysine demethylases (KDMs), and aim to develop and validate cell- based assays targeting both KMTs and KDMs. These assays, based on a three-hybrid split luciferase system, are reversible allowing dose dependent quantification of inhibitor binding. These efforts are both significant and innovative as they can report on the direct binding of a drug to the target protein at its intended site of action, thereby facilitating the generation of lead therapeutic candidates and identification of chemical probes for studying histone biology and pathways.

项目总结