Repurposing kinase inhibitor chemotypes as antimalarials
Repurposing kinase inhibitor chemotypes as antimalarials
批准号:
10599254
负责人:
Kelly Chibale
金额:
$29.07万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-04-03 至 2025-03-31
关键词:
AccountingAffectAffinityAfricanAntimalarialsArtemisininsBiologicalBiological AssayBloodCause of DeathCellsCessation of lifeChemicalsChildClinicalCollaborationsCombined Modality TherapyComputer AssistedCountryDataDevelopmentDiseaseDrug DesignDrug KineticsDrug TargetingDrug resistanceDrug usageEnsureGeneticGenomicsGoalsHealthHumanInfectionKnowledgeLeadLibrariesLife Cycle StagesMalariaModelingModificationMonitorOralOutcomeParasitesPharmaceutical ChemistryPhenotypePhosphotransferasesPlasmodiumPlasmodium falciparumProteinsProteomicsQuality of lifeReagentRecommendationReportingResearchResistanceRoleSCID MiceSafetySeriesStructureSymptomsTechniquesTestingToxic effectTraditional MedicineWorkWorld Health Organizationasexualcancer therapycombatdrug candidatedrug developmentdrug discoverydrug metabolismexperimental studyhuman diseasehumanized mouseimprovedin vivoin vivo Modelinhibitorinsightinterestkinase inhibitorlead optimizationmalaria infectionmarginalized communitymouse modelnew therapeutic targetnovelnovel therapeuticsscreeningstructural genomicssuccesstransmission process
中文摘要
摘要
英文摘要
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.
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Repurposing kinase inhibitor chemotypes as antimalarials
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批准号:9983240
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项目类别:
-
资助金额:$35.0万
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财政年份:2020
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负责人:Kelly Chibale
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依托单位:
Repurposing kinase inhibitor chemotypes as antimalarials
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批准号:10375516
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项目类别:
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资助金额:$30.41万
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财政年份:2020
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负责人:Kelly Chibale
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依托单位:
海外基金