Hit-to-lead discovery for sleeping sickness via industry-academic partnership

通过产学合作取得昏睡病的先导发现

基本信息

批准号：
8978292
负责人：
Miguel A Navarro
金额：
$ 47.54万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-04 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8978292
关键词：
Address Affect Africa South of the Sahara African Trypanosomiasis Animal Model Biological Availability Blood Blood - brain barrier anatomy Blood Circulation Brain Injuries Cardiotoxicity Cells Central Nervous System Agents Chemical Structure Chemicals Clinical Collaborations Communities Cytochrome P450 Data Databases Development Disease Dose Drug Evaluation Drug Industry Drug Interactions Drug Kinetics Drug toxicity Ensure Enzymes Equilibrium Foundations Funding Goals Growth Health HepG2 Human Human Resources Industry Infection Lead Ligands Measures Melarsoprol Metabolic Methods Modeling Mus National Research Council Neuraxis Oral Outcome Parasites Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Phosphotransferases Principal Investigator Property Regimen Research Research Personnel Sepsis Series Sorting - Cell Movement Staging Testing Time Toxic effect Translating Trypanosoma brucei brucei Trypanosomiasis Universities Work data portal data sharing disability-adjusted life years drug discovery drug metabolism genetic profiling high throughput screening in vivo inhibitor/antagonist interest lead series meetings mortality mouse model neglect neglected tropical diseases novel therapeutics pre-clinical process optimization programs research study screening

项目摘要

DESCRIPTION (provided by applicant): Human African trypanosomiasis (HAT) is a neglected tropical disease (NTD) that is caused by the protozoan parasite Trypanosoma brucei, and for which current drugs have poor efficacy or toxicity profiles. Discovery of new drugs for this fatal disease has been hindered by a lack of high quality lead compounds for optimization. In a unique industrial-academic collaboration, the Principal Investigators have been collaborating with GlaxoSmithKline (GSK) in a project funded by the Tres Cantos Open Lab Foundation, which has enabled the high-throughput screen (HTS) of over 46,000 kinase-targeted inhibitor compounds against T brucei cells. The project resulted in discovery of 797 potent (T brucei EC50< 1 μM) and selective (> 100-fold over HepG2 cells) that were sorted into 59 structural clusters, plus 53 singleton compounds. With a desire to prioritize this large set of hit compounds, these compounds were assessed for their rate of action, reversibility of growth inhibition, and for a wide range of physicochemical and drug metabolism properties (computed and measured). This proposal outlines a hit-to-lead medicinal chemistry program that will optimize four of the highest- priority hit clusters, plus a highly potent singleton compound that shows efficacy in T brucei bloodstream infections in mice. Optimization will result in the delivery of high-quality lead compounds from each of these five chemical classes, and these leads will meet stringent profiles of cellular potency and selectivity, blood- brain barrier permeability, physicochemical and metabolic properties, and pharmacokinetic properties in mice. Central nervous system (CNS) exposure is of paramount importance. Furthermore, these lead series will display in vivo efficacy in murine models of bloodstream and CNS T brucei infections. The optimization program described in this proposal will be performed under the continuing collaboration between the PIs at Northeastern University and the Spanish National Council for Research (CSIC), with critical contributions of expertise and drug metabolism and physicochemical properties experiments from GSK. We have developed and implemented a testing funnel that ensures that the optimization process will address the most critical lead criteria. With an interest in seeding others' work in HAT drug discovery, all data generated in the course of this program will be disclosed in real time via a searchable database that can be accessed by NTD researchers world-wide. Taken together, we believe that this represents an unprecedented resource for HAT drug discovery. In the end, this project will deliver (a) multiple lead compounds for HAT that meet well-defined Lead Criteria; (b) broader profiling of lead compounds against more stringent Candidate Criteria (enabling evaluation by the Drugs for Neglected Disease Initiative (DNDi) for potential further advancement. In that way, we intend to help fill the early preclinical drug discovery pipeline for HAT.

描述（由应用程序提供）：非洲人类锥虫病（HAT）是由原生动物寄生虫锥虫引起的被忽视的热带疾病（NTD），目前的药物的效率较差或毒性概况。由于缺乏优化的优质铅化合物而阻碍了这种致命疾病的新药物的发现。在独特的工业学术合作中，首席研究人员在由TRES Cantos Open Lab Foundation资助的项目中与GlaxoSmithKline（GSK）合作，该项目使超过46,000个Kinase Kinase-tarase-tarase-tarze-tarke-tarke屏幕（HTS）具有抗T brucei Cells抗Trabor抑制剂化合物。该项目导致发现了797个电势（T Brucei EC50 <1μm）和选择性（在HEPG2细胞上> 100倍），这些电位分为59个结构簇，再加上53个单胎化合物。渴望优先考虑这种大量的HIT化合物，这些化合物的作用速度，生长抑制的可逆性以及广泛的物理化学和药物代谢特性（计算和测量）评估了这些化合物。该提案概述了一项命中率对铅的药物化学计划，该计划将优化四个最优先的命中簇，再加上高潜在的单胎化合物，该化合物表明小鼠T Brucei Blodstream感染的效率。优化将导致交付来自这五种化学类别的每种化合物的高质量铅化合物，这些铅将符合细胞效力和选择性，血脑屏障的渗透性，物理和代谢特性以及小鼠的药代特性的严格概况。中枢神经系统（CNS）暴露至关重要。此外，这些铅系列将在血液和CNS T brucei感染的鼠模型中显示体内效率。本提案中描述的优化计划将在东北大学PIS与西班牙国家研究委员会（CSIC）之间的持续合作下进行，并提供了来自GSK的专业知识和药物代谢和物理性质实验的重要贡献。我们已经开发并实施了一个测试漏斗，以确保优化过程将解决最关键的铅标准。有兴趣播种他人的帽子探索工作，所有数据均产生该程序的过程将通过全球NTD研究人员访问的可搜索数据库实时披露。综上所述，我们认为这代表了帽子药物发现的前所未有的资源。最后，该项目将提供（a）符合定义明确标准的帽子的多种铅化合物；（b）针对更严格的候选标准的铅化合物的更广泛分析（通过被忽视的疾病倡议（DNDI）进行评估，以进一步进一步进步。这样，我们打算帮助填补早期的临床前药物发现管道的HAT。