Phase II year
2020
(last award dollars: 2021)
Phase II Amount
$1,756,240
The genome of Plasmodium falciparum, the species responsible for most mortality in malaria, is predicted to encode 86-99 protein kinases. Of these, 36 kinases are expressed in the asexual stage of the parasites life-cycle, which is responsible for the pathology associated with the disease. Using our proprietary KinaseSeeker technology, we have recently developed assays against 11 Plasmodium falciparum kinases, which are expressed in the asexual stage. Screening a small-molecule kinase inhibitor library has revealed several chemically tractable chemotypes that bind P. falciparum kinases with sub-micromolar affinity. In this application, using a target-based approach, we aim to utilize the chemotypes identified from our screening data, as starting points for development of potent and selective antimalarial agents. In addition, we will use the already commercialized P. falciparum kinase assays, to identify targets for potential kinase inhibitors that have been shown to be active in phenotypic screens against the parasite. The different series of compounds will then be further optimized for potency and selectivity to deliver leads for new antimalarials and improve human health.
Public Health Relevance Statement: Project Narrative Malaria, a deadly disease caused by a parasite Plasmodium, was responsible for morbidity in 200 million and resulting deaths in 435,000 people globally in 2017. Drug resistance is emerging against current treatments, making them ineffective. Thus, there is a dire need for new drugs. The purpose of our application is to develop antimalarial drugs targeted against Plasmodium kinases.
Project Terms: Affect; Affinity; Anopheles Genus; Antimalarials; Artemisinins; asexual; base; Binding; Biological Assay; Biology; candidate selection; Cessation of life; Chemicals; Clinical; clinical candidate; Collection; combat; Combined Modality Therapy; Communities; Country; CSNK1A1 gene; Culicidae; Data; design; Development; Disease; disorder control; drug development; Drug resistance; Drug Targeting; Erythrocytes; genome sequencing; Goals; Health; Human; Human Bites; improved; in vivo; Incidence; Infection; inhibitor/antagonist; Investments; kinase inhibitor; knockout gene; Lead; Libraries; Life Cycle Stages; Luciferases; Malaria; Maps; Medicine; member; Morbidity - disease rate; mortality; next generation; novel; novel therapeutics; open source; Parasites; Pathology; Pharmaceutical Preparations; Phase; Phenotype; phosphoproteomics; Phosphotransferases; Plasmodium; Plasmodium falciparum; Plasmodium falciparum genome; Plasmodium vivax; Private Sector; programs; Protein Kinase; protein kinase inhibitor; Public Sector; Publishing; Reporting; Research; Resistance; scaffold; screening; Series; small molecule; Technology; tool; Trees
