Repurposing kinase inhibitor chemotypes as antimalarials

摘要 疟疾仍然是许多国家的主要死亡原因， 青蒿素类复方疗法是最后一道防线，对疟疾控制构成巨大问题。 为了阻止耐药性的传播并促进消灭疟疾， 对临床上使用的药物有效，并且对疟原虫寄生虫的多个阶段有效 生命周期迫切需要。疟原虫激酶，对寄生虫的两个无性血液阶段至关重要 导致疾病症状的生命周期和导致感染传播的性阶段， 已经被确定为药物发现的脆弱目标。人类激酶抑制剂的成功 癌症和其他人类疾病的治疗产生了大量的化学物质， 生物学数据可以深入了解激酶的功能，结构和选择性，这些数据可以用于 开发抗疟疾的激酶抑制剂。该项目旨在确定一种新的化合物， 通过重新利用人激酶抑制剂化学型在疟疾感染的体内模型中有效。这 将包括两个高级化合物系列的优化，源于激酶导向化合物 文库，显示出有效的抗疟原虫活性。此外，文库的表型全细胞筛选 选择性人类激酶抑制剂将进行针对恶性疟原虫无性血液阶段 寄生虫，以确定额外的化学型，进入命中铅药物化学优化。 将采用互补的遗传学和蛋白质组学靶点鉴定方法， 具有有效的全细胞活性的化合物的靶点。在可测定的疟原虫激酶被 作为主要靶标，命中-先导优化将监测全细胞和靶标活性， 结合计算机辅助药物设计方法，以优化相对于 人激酶脱靶。基于跨多个阶段的抗疟原虫活性的有前景的化合物 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。除了发现一种新的抗疟疾药物外，这项研究还发现， 将着手确定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.