Repurposing kinase inhibitor chemotypes as antimalarials

摘要 疟疾仍然是许多国家的主要死亡原因，出现了对疟疾的耐药性。 基于青蒿素的联合疗法是最后一道防线，对疟疾控制构成了一个巨大的问题。 为了阻止耐药性的传播并为消除疟疾做出贡献，采用不同模式的新疗法 对临床使用的药物的作用，以及对疟原虫多个阶段有效的药物 生命周期是迫切需要的。疟原虫激酶，对寄生虫的两个无性血液阶段都是必不可少的 负责疾病症状的生命周期和负责传播感染的性阶段， 已被确定为药物发现的脆弱目标。人类激酶抑制剂在治疗癌症方面的成功 癌症和其他人类疾病的治疗产生了大量的化学物质和 生物数据提供了对激酶功能、结构和选择性的洞察，这些数据可以被利用来 抗击疟疾的激酶抑制剂的开发。该项目旨在鉴定一种新型的口服化合物。 在疟疾感染体内模型中，通过改变人类激酶抑制物化学类型的用途而有效。这 将包括两个高级化合物系列的优化，这些化合物来自于激酶导向的化合物 显示出强大的抗疟原虫活性的文库。另外，一种文库的表型全细胞筛选 将对恶性疟原虫无性血液期进行选择性人类激酶抑制剂的研究 寄生虫识别更多的化学类型，进入药物化学优化。 将采用互补的遗传和蛋白质组靶标识别方法来识别 具有强大全细胞活性的化合物的目标/S。在可检测的疟原虫激酶是 被确定为主要目标的命中到领先优化将监控整个单元和目标活动， 结合计算机辅助药物设计方法，以优化相对于 人体激活酶偏离靶点。基于多个阶段的抗疟原虫活性的有希望的化合物 该药物的生命周期、良好的药物代谢和药代动力学特征以及低毒性将在 疟疾感染的人源化小鼠模型。除了确定一种新的抗疟疾药物外，这项研究还 将着手识别和化学验证新的疟原虫药物靶点。

Abstract Malaria continues to be a leading cause of death in many countries and the emergence of drug resistance to artemisinin-based combination therapy, the last line of defence, poses a huge problem for malaria control. To halt the spread of drug resistance and contribute to malaria elimination, new therapies with different modes of action to drugs used clinically, and that are effective against multiple stages of the Plasmodium parasite life-cycle are urgently required. Plasmodium kinases, essential to both asexual blood stages of the parasite life-cycle responsible for disease symptoms and the sexual stages responsible for transmission of infection, have been identified as vulnerable targets for drug discovery. The success of human kinase inhibitors for the treatment of cancer and other human diseases has resulted in a large amount of chemical matter and biological data giving insight into kinase function, structure and selectivity, which can be harnessed for the development of kinase inhibitors against malaria. This project aims to identify a novel compound that is orally efficacious in an in vivo model of malaria infection by repurposing human kinase inhibitor chemotypes. This will include the optimization of two advanced compound series, originating from kinase-directed compound libraries, that display potent antiplasmodium activity. In addition, a phenotypic whole cell screen of a library of selective human kinase inhibitors will be carried out against Plasmodium falciparum asexual blood-stage parasites to identify additional chemotypes to enter hit-to-lead medicinal chemistry optimization. Complementary genetic and proteomic target-identification approaches will be carried out to identify the target/s of compounds with potent whole cell activity. In cases where assayable Plasmodium kinases are identified as the primary targets, hit-to-lead optimization will monitor both whole-cell and target activities, incorporating computer-aided drug design approaches to optimise for potency and selectivity relative to human kinase off-targets. Promising compounds based on antiplasmodium activity across multiple stages of the lifecycle, favorable drug metabolism and pharmacokinetic profiles and low toxicity, will be tested in a humanised mouse model of malaria infection. In addition to identifying a novel antimalarial drug, this research will set out to identify and chemically validate novel Plasmodium drug targets.