Repurposing human kinase inhibitor chemotypes for Neglected Tropical Diseases

重新利用人类激酶抑制剂化学型来治疗被忽视的热带病

• 批准号: 10211513
• 负责人: MICHAEL P POLLASTRI
• 金额: $ 46.42万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-04 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10211513
• 关键词: Acute; Address; Africa; African Trypanosomiasis; Animals; Arginine; Asia; Biological Assay; Blood - brain barrier anatomy; Cells; Central America; Chagas Disease; Chemicals; Collaborations; Communicable Diseases; Complex; Computer Assisted; Country; Cytochrome P450; Data; Development; Disease; Disease model; Drug Combinations; Drug Industry; Drug Kinetics; Ensure; Enzymes; Fingerprint; Funding; G-Protein-Coupled Receptors; Generations; Genetic; Goals; Health; HepG2; Human; Industrialization; Infection; Investments; Knock-out; Latin America; Lead; Life; Medicine; Metabolic; Modeling; Molecular Mechanisms of Action; Mus; Nature; Parasites; Parasitic Diseases; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Phosphotransferases; Production; Property; Proteomics; Recombinant Proteins; Resistance; Risk; Series; Source; Structure; Testing; Therapeutic Uses; Toxic effect; Treatment Failure; Treatment Protocols; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosoma cruzi; Validation; Work; World Health Organization; analog; blood-brain barrier permeabilization; clinical candidate; cost; drug discovery; drug metabolism; experimental study; follow-up; genome sequencing; high throughput screening; in silico; in vivo; in vivo Model; inhibitor/antagonist; interest; kinase inhibitor; lead series; mouse model; mutant; neglect; neglected tropical diseases; novel therapeutics; overexpression; pathogen; population migration; pre-clinical; process optimization; programs; response; side effect; synergism; whole genome

SUMMARY/ABSTRACT Human African trypanosomiasis (HAT) and Chagas disease (CD) are neglected tropical diseases (NTDs). Current drugs show increasing numbers of treatment failure, low efficacy, difficult treatment regimens or severe side effects. In a unique industrial-academic collaboration, the PIs, in collaboration with GSK, ran a high-throughput screen (HTS) of ~46,000 kinase-targeted inhibitors against Trypanosoma brucei, the causative agent of HAT. This resulted in the discovery of 797 potent (T brucei EC50<1 μM; pEC50 6) and selective hits (>100-fold over HepG2 cells) that were sorted into 59 structural clusters, plus 53 singletons. 14 chemotypes including 13 clusters and 1 singleton have been explored for their structure-activity and structure-property relationships. A “parasite-hopping” approach has identified six of these with interesting activity against T cruzi (CD). This competitive renewal outlines a hit-to-lead medicinal chemistry program that will continue to optimize high-priority hit clusters from the original HTS. These have been identified through re-analysis of the original HTS data to place an emphasis on compounds that are cidal and predicted to cross the blood-brain barrier (BBB) which is essential to treat stage 2 of HAT. Additionally, we will employ computer-aided drug discovery to further explore those chemotypes for which we have identified a putative target. We will also perform hit-to-lead medicinal chemistry optimization on the six chemotypes that have been identified as of interest for T cruzi. We will also look for synergistic effects between clusters that have complementary activity profiles (e.g. slow acting, cidal in nature, and fast acting, static in nature) and in combination with standard trypanocidal drugs. Optimization will result in the delivery of high-quality lead compounds from each of these chemical classes, and the lead compounds will meet stringent profiles of cellular potency and selectivity, BBB permeability, physicochemical and metabolic properties, and pharmacokinetic properties in mice depending on the disease targeted. Furthermore, these lead series will display in vivo efficacy in the murine models of disease. The optimization program will be performed under the continuing collaboration between NEU and CSIC, with critical contributions of expertise in drug metabolism and physicochemical properties experiments from AstraZeneca and UCSD. We have developed and implemented a testing funnel that ensures that the optimization process will address the most critical lead criteria. Finally, we will perform the target identification and mode of action studies by different approaches including chemical proteomics, induction of resistance and whole genome sequencing and metabolic fingerprinting. This project will deliver (a) multiple lead compounds for HAT and CD that meet well-defined Lead Criteria; (b) broader profiling of lead compounds against more stringent Candidate Criteria; (c) identification of target for lead series or compound. In this way, we intend to help fill the pre-clinical candidate pipeline for HAT and CD.

总结/摘要 人类非洲锥虫病和恰加斯病是被忽视的热带疾病 （NTD）。目前的药物治疗失败、疗效低下、治疗方案困难等问题日益增多 或者严重的副作用在一次独特的工业-学术合作中，PI与GSK合作， 高通量筛选（HTS）约46，000种针对布氏锥虫的激酶靶向抑制剂， HAT的代理人。结果发现了797个有效的（布氏锥虫EC 50 <1 μM; pEC 50 6）和选择性的命中 （> HepG 2细胞的100倍），其被分选成59个结构簇，加上53个单例。14种化学型 包括13个簇合物和1个单体化合物，对其构效关系和结构性质进行了研究 关系。一种“寄生虫跳跃”的方法已经确定了其中六种对克氏锥虫具有有趣的活性 （CD）。 这种竞争性的更新概述了一个命中领先的药物化学计划，将继续优化 原始HTS中的高优先级命中簇。这些都是通过重新分析原 HTS数据重点关注具有杀灭作用并预计可穿过血脑屏障（BBB）的化合物 这对于治疗HAT的第二阶段是必需的。此外，我们将采用计算机辅助药物发现， 探索那些我们已经确定了假定靶点的化学型。我们还将进行一击领先 药物化学优化的六个化学型已确定为感兴趣的克氏锥虫。我们 还将寻找具有互补活性分布的簇之间的协同效应（例如缓慢作用， 性质上是杀锥虫的，并且性质上是快速作用的、静态的），并且与标准的杀锥虫药物组合。 优化将导致从这些化学品中的每一种提供高质量的先导化合物 类，并且先导化合物将满足细胞效力和选择性，BBB渗透性， 理化和代谢特性，以及根据疾病在小鼠中的药代动力学特性 针对性地此外，这些先导化合物系列将在疾病的鼠模型中显示体内功效。 优化计划将在NEU和CSIC之间的持续合作下进行， 在药物代谢和理化性质实验方面的专业知识的重要贡献， 阿斯利康和加州大学圣地亚哥分校。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潜在客户标准。最后，我们将执行目标识别 通过不同的方法，包括化学蛋白质组学，诱导抗性， 全基因组测序和代谢指纹分析。 该项目将提供（a）符合明确规定的铅标准的HAT和CD的多种铅化合物; (b)（c）根据更严格的候选标准，对先导化合物进行更广泛的分析; 铅系或铅化合物。通过这种方式，我们打算帮助填补HAT和CD的临床前候选人管道。