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

• 批准号: 10594538
• 负责人: Margaret A. Phillips
• 金额: $ 73.72万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 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/10594538
• 关键词: ADME Study; African; Ames Assay; Amides; Antimalarials; Antiparasitic Agents; 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; acquired drug resistance; analog; azetidine; 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 blocking; whole genome

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，威胁着全球近 50% 的地区 人口，每年导致超过 400,000 人死亡，其中大部分是非洲幼儿。没有 有效的疫苗，并且通过杀虫剂和药物的结合来控制该疾病 治疗和化学预防。寄生虫获得耐药性的不懈能力需要 维持新候选药物的持续研发。我们试图找出新的化学原料 通过针对红细胞 P 期的表型筛选发现新的抗疟疾药物的要点。 恶性疟原虫。我们对新收购的（2017 年）100K 化学库进行了高通量筛选 理由是，由于它是最近购买的，因此它可能包含以前没有的新化学空间 筛选。作为点击验证过程的一部分，我们根据以下内容优先考虑屏幕上的点击 实验测量：1) 相对于寄生虫对两种细胞系的效力，2) 相对于人类细胞的选择性 线，3）化学物质的新颖性，4）寄生虫杀灭率（中速和快速杀灭是理想的）和5）体外 ADME 特性包括代谢稳定性和溶解度。我们确定了 16 个符合我们要求的化学品系列 新颖的目标，并从中选择了 3 个系列作为热门化学。这些包括哌啶 甲酰胺系列 (Alchm18) 具有中等杀灭率，良好的起始效力 (P. falciparum 3D7 EC50 <100 nM)，以及强大的体外和体内 ADME 特性； a 基于四唑的系列 (Alchm3) 显示出快速杀灭动力学，并且是氮杂环丁酰胺 (Alchm17)，具有良好的效力和溶解度。我们已经验证了 通过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 该提案的目的是对这三个系列进行从命中到先导的化学反应，以评估它们的生物学特征， 并进行研究以确定其目标。最强系列将优先获得全面领先 优化。我们的项目团队由 Phillips（寄生虫生物学）、Ready（药物化学）和 Charman 组成 (ADME/PK) 经验丰富，并且有着长期的合作记录。该项目也将是一个 与 Medicines for Malaria Venture (MMV) 合作，MMV 将提供实物支持和获取 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 将对三种新化学系列的可开发性有实质性的新见解，我们将验证 到另外三个新的抗疟疾目标，我们将取得三种化学物质中最强的一种 系列通过先导化合物优化来确定潜在的临床前开发候选药物。