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High-Throughput Screening Platform for Cancer Drug Discovery

癌症药物发现的高通量筛选平台

基本信息

批准号：
10163816
负责人：
Laurie L. Parker
金额：
$ 66.9万
依托单位：
PALO ALTO RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10163816
关键词：
Advanced Development Affinity Antineoplastic Agents Binding Biochemical Reaction Biological Assay Biological Models Bromodomain Buffers CREBBP gene Calorimetry Consumption Data Data Analyses Detection Enzymes Goals Gold Grant Histones Hour Individual Label Libraries Ligands Lighting Liquid substance Malignant Neoplasms Measurement Measures Methods Microfluidics Monitor Morphologic artifacts Oils Optics Peptides Performance Phosphopeptides Phosphotransferases Positioning Attribute Proteins Reaction Reagent Research Personnel Resolution SYK gene Sampling Screening procedure Specificity System Systems Development Techniques Technology Temperature Therapeutic Thermodynamics Time Titrations Validation Water aqueous assay development base biophysical properties cancer therapy drug development drug discovery enthalpy enzyme activity enzyme substrate experimental study high throughput screening high-throughput drug screening histone acetyltransferase improved inhibitor/antagonist instrument instrumentation interest liquid crystal millisecond particle receptor screening small molecule src Homology Region 2 Domain stoichiometry targeted treatment therapeutic target tool development

项目摘要

Project Summary Targeted therapies have shown great promise in the treatment of cancer. High-throughput screening (HTS) campaigns have often relied on assays using labeled ligands or enzyme substrates. Artifacts associated with labeling have led to the erroneous identification of compounds that act in on the labeled substrate rather than the intended target. A label-free, solution-based HTS method will facilitate identification of compounds acting specifically on the intended targets. The goals of this proposed project are to advance development and validate this calorimetry platform as an accessible approach for high throughput ITC analysis, demonstrating its advantages to study a variety of cancer therapeutic targets. To achieve this goal, we will improve mixing of reagents in droplets, multiplex temperature readout from individual droplets, automate fluidic handling and data analysis, and validate the applicability of the improved technology to study: 1) SH2 domain/phosphopeptide interactions, 2) spleen tyrosine kinase (Syk) enzyme activity, and 3) Bromodomain/acetylated histone peptide interactions, further applied in small molecule screening. The realization of the spectro-optical calorimetry technology platform will enable full thermodynamic characterization of binding and enzymatic reactions at the throughput of 1536-well plate assays but with significantly reduced assay development time and larger numbers of repeats and analyte concentrations. The combination of increased throughput and reduced sample consumption will change the way researchers view calorimetry: rather than being seen as a technique for a limited number of high-value measurements, it will be viewed as a primary screening method for cancer therapeutic targets.

项目总结