Repurposing kinase inhibitor chemotypes as antimalarials

将激酶抑制剂化学型重新用作抗疟药

基本信息

批准号：
10375516
负责人：
Kelly Chibale
金额：
$ 30.41万
依托单位：
UNIVERSITY OF CAPE TOWN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-03 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10375516
关键词：
Accounting Affect Affinity African Antimalarials Artemisinins Biological Biological Assay Blood Cause of Death Cells Cessation of life Chemicals Child Clinical Collaborations Combined Modality Therapy Computer Assisted Country Data Development Disease Drug Design Drug Kinetics Drug Targeting Drug resistance Drug usage Ensure Genetic Goals Health Human Infection Knowledge Lead Libraries Life Cycle Stages Malaria Modeling Modification Monitor Oral Outcome Parasites Pharmaceutical Chemistry Phenotype Phosphotransferases Plasmodium Plasmodium falciparum Proteins Proteomics Quality of life Reagent Reporting Research Resistance Rivers Role SCID Mice Safety Series Structure Symptoms Techniques Testing Toxic effect Work World Health Organization asexual base cancer therapy combat drug candidate drug development drug discovery drug metabolism experimental study human disease humanized mouse improved in vivo in vivo Model inhibitor insight interest kinase inhibitor lead optimization malaria infection marginalized community mouse model new therapeutic target novel novel therapeutics screening structural genomics success transmission process

项目摘要

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.

抽象的在许多国家，疟疾仍然是死亡的主要原因，并且耐药地出现了基于青蒿素的结合疗法是最后的防御疗法，这给疟疾控制带来了一个巨大的问题。为了停止耐药性的传播并导致消除疟疾，具有不同模式的新疗法临床上使用的药物作用，它们在疟原虫的多个阶段有效迫切需要生命周期。疟原虫激酶，对寄生虫的两个无性血液阶段必不可少负责疾病症状的生命周期和导致感染传播的性阶段已被确定为弱势药物发现目标。人类激酶抑制剂的成功癌症和其他人类疾病的治疗已导致大量的化学物质和生物学数据可深入了解激酶功能，结构和选择性，可以利用激酶抑制剂抗疟疾的发展。该项目旨在识别口头的新颖化合物通过重新利用人类激酶抑制剂化学型，在体内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，源自激酶定向化合物图书馆，表现出有效的抗血流活性。另外，库的表型全细胞屏幕选择性人类激酶抑制剂将针对恶性疟原虫无性血液阶段进行寄生虫确定其他化学型，以进入命中率铅化学化学优化。将采用互补的遗传和蛋白质组学目标识别方法来确定具有有效全细胞活性的化合物的靶标。如果可测估的疟原虫激酶是被确定为主要目标，HIT-to-Lead优化将监视整个细胞和目标活动，合并计算机辅助的药物设计方法，以优化相对于效力和选择性人类激酶离靶。基于多个阶段的抗张流活性的有希望的化合物生命周期，有利的药物代谢和药代动力学特征以及低毒性将在A中进行测试人类疟疾感染的小鼠模型。除了确定一种新型抗疟药外，这项研究将着手识别和化学验证新型疟原虫药物靶标。