Repurposing human kinase inhibitor chemotypes for Neglected Tropical Diseases

摘要/摘要 人类非洲锥虫病(HAT)和恰加斯病(CD)是被忽视的热带病 (NTDS)。目前的药物显示出越来越多的治疗失败、疗效低、治疗方案困难的情况 或者严重的副作用。在一次独特的产学合作中，PIS与GSK合作，运行了一项 高通量筛选~46,000个针对布鲁氏锥虫的激酶靶向抑制物 HAT的代理人。这导致了797个有效的(T brucei EC50&lt；1μM；pEC506)和选择性打击的发现 (&gt；是HepG2细胞的100倍)，它们被分成59个结构簇，外加53个单体。14种化学型 其中包括13个簇合物和1个单态化合物的结构-活性和结构-性质 两性关系。一种“寄生虫跳跃”的方法已经确定了其中六种具有对抗T ruzi的有趣活动。 (CD)。 这一竞争性更新概述了一个将继续优化的点击到领先的药物化学计划 来自原始HTS的高优先级热门集群。这些都是通过对原始文件的重新分析而确定的 HTS数据将重点放在具有杀伤性并预计会穿过血脑屏障(BBB)的化合物上 这对于治疗HAT的第二阶段是必不可少的。此外，我们将利用计算机辅助药物发现，以进一步 探索那些我们已经确定了可能的靶点的化学类型。我们还将表演Hit-to-Lead 对已确定的六种化学类型的药物化学优化已被确定为T ruzi。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，慢作用， 杀伤力强、作用快、静止性强)，并与标准的杀锥虫药物联合使用。 优化将导致从这些化学品中的每一种提供高质量的铅化合物 先导化合物将满足严格的细胞效力和选择性，血脑屏障渗透性， 取决于疾病的小鼠的物理化学和代谢特性以及药代动力学特性 有针对性的。此外，这些铅系列将在小鼠疾病模型中显示体内疗效。 优化计划将在北大和中投的持续合作下进行，具有 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UCSD。我们开发并实现了一个测试漏斗，以确保 优化流程将解决最关键的领先标准。最后，我们将进行目标识别 以及不同方法的作用模式研究，包括化学蛋白质组学，抗性诱导和 全基因组测序和代谢指纹分析。 该项目将提供(A)符合明确定义的铅标准的HAT和Cd的多种先导化合物； (B)根据更严格的候选标准对先导化合物进行更广泛的剖析；(C)确定 铅系列或化合物。通过这种方式，我们打算帮助填补HAT和CD的临床前候选管道。

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.