Optimization of novel phenotypic screening hits for treatment of Malaria

用于治疗疟疾的新型表型筛选靶标的优化

基本信息

批准号：
10652726
负责人：
Margaret A. Phillips
金额：
$ 6.25万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10652726
关键词：
ADME Study African Ames Assay Amides Antimalarials Biochemical Biological Biological Assay Biology Blood Cell Line Cells Cessation of life Chemicals Chemistry Chemoprevention Child Clinical Communicable Diseases Data Development Disease Dose Drug Kinetics Drug resistance Erythrocytes Evaluation Excretory function Genetic Goals Half-Life HepG2 Human Human Cell Line In Vitro Insecticides Ion Channel Kinetics Lead Life Cycle Stages Liver Malaria Mammalian Cell Mass Spectrum Analysis Measures Medicine Metabolic Metabolism Modeling Molecular Target Mus Parasite resistance Parasites Parents Pharmaceutical Chemistry Pharmaceutical Preparations Phenotype Plasmodium Plasmodium falciparum Plasmodium vivax Population Positioning Attribute Process Property Proteomics Protocols documentation Publishing Rattus Recrudescences Resistance Risk SCID Mice Safety Series Solubility Structure Testing Tetrazoles Time Vaccines Validation Work absorption analog azetidine base clinical candidate clinical development combat comparative efficacy crosslink drug candidate drug discovery drug-sensitive experience genome sequencing high throughput screening human disease in vivo insight lead optimization mortality mouse model multidisciplinary novel novel therapeutics piperidine pre-clinical preclinical development pressure programs safety assessment scaffold screening small molecule libraries transmission process whole genome

项目摘要

Project Summary. Malaria remains one of the most serious infectious diseases, globally threatening nearly 50% of the world population, and leading to >400,000 deaths annually, mostly among young African children. There are no effective vaccines and the disease is managed through a combination of insecticides and drugs for both treatment and chemoprevention. The relentless ability of the parasite to acquire drug resistance necessitates that a continual pipeline of new drug candidates is maintained. We sought to identify novel chemical starting points for the discovery of new anti-malarial drugs by phenotypic screening against erythrocytic stage P. falciparum. We undertook a high-throughput screen of a newly acquired (in 2017) 100K chemical library reasoning that since it was recently purchased it might contain new chemical space that had not been previously screened. As part of our hit validation process we prioritized hits from the screen based on the following experimental measures: 1) potency versus the parasite against two cell lines, 2) selectivity versus a human cell line, 3) novelty of the chemical matter, 4) parasite kill rate (medium and fast kill being desirable) and 5) in vitro ADME properties including metabolic stability and solubility. We identified 16 chemical series that met our objectives of novelty and from these have selected 3 series for hit to lead chemistry. These include a piperidine carboxamide series (Alchm18) that has a moderate rate of kill, good starting potency (P. falciparum 3D7 EC50 <100 nM), and strong starting in vitro and in vivo ADME properties; a a tetrazole-based series (Alchm3) that shows fast kill kinetics, and a an azetidine amide (Alchm17), with good potency and solubility. We have validated synthetic strategies for all three series through synthesis of both the parent compound and analogs. The goal of this proposal is to conduct hit-to-lead chemistry on these three series, to evaluate their biological profiles, and to perform studies to identify their targets. The strongest series will then be prioritized for full scale lead optimization. Our project team of Phillips (parasite biology), Ready (medicinal chemistry) and Charman (ADME/PK) is highly experienced and has a long track record of working together. The project will also be a collaborative effort with the Medicines for Malaria Venture (MMV) who will provide in kind support and access to their in vitro and in vivo parasite efficacy models and project oversight. Upon completion of this proposal we will have substantial new insight into the developability of three new chemical series, we will have validated up to three additional new anti-malarial targets, and we will have progressed the strongest of our three chemical series through lead optimization to identify a potential preclinical development candidate.

项目摘要。疟疾仍然是最严重的传染病之一，在全球范围内威胁着近50％人口，每年导致40万人死亡，主要是在非洲年轻儿童中。没有有效的疫苗和该疾病是通过杀虫剂和药物的组合来治疗的治疗和化学预防。寄生虫获得耐药性的无情能力是必需的维持了新的候选药物的持续管道。我们试图确定新型化学开始通过针对红细胞阶段的表型筛选发现新的抗疟疾药物的点。恶意。我们在新收购（2017年）100K化学库的高通量屏幕上进行了高通量屏幕推理，由于最近被购买了，它可能包含以前从未有过的新化学空间筛选。作为命中验证过程的一部分，我们根据以下实验措施：1）效力与两个细胞系的寄生虫相对于寄生虫，2）选择性与人类细胞行，3）化学物质的新颖性，4）寄生虫杀伤率（中等和快速杀死）和5）体外 ADME特性，包括代谢稳定性和溶解度。我们确定了16个化学系列新颖性的目标以及从中选择了3系以铅化学的命中率。这些包括哌啶羧酰胺系列（ALCHM18）具有适度的杀伤率，良好的起始效力（P. falciparum 3D7 EC50 <100 nm），并且在体外和体内adme属性中有强大的启动；一个基于四唑的系列（ALCHM3）显示快速杀死动力学和偶氮胺酰胺（ALCHM17），具有良好的效力和溶解度。我们已经验证了通过综合母体化合物和类似物的合成，所有三个系列的合成策略。目标该提议的内容是对这三个系列进行命中率化学，以评估其生物学特征，即并进行研究以识别其目标。然后，最强的系列将优先考虑全尺度线索优化。我们的Phillips项目团队（寄生虫生物学），Ready（药物化学）和Charman （ADME/PK）经验丰富，并且在共同努力方面有很长的记录。该项目也将是一个与疟疾风险投资（MMV）的协作努力，他们将提供善良的支持和访问他们的体外和体内寄生虫功效模型和项目监督。完成此提案后，我们将对三个新化学系列的发展性有实质性的新见解，我们将验证到另外三个新的反疟疾目标，我们将进步三种化学物质中的最强通过铅优化串联，以识别潜在的临床前发展候选者。