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Discovery of Potent Antimalarial Type II Kinase Inhibitors with Selectivity over Human Kinases
Lushun Wang1, Monica J Bohmer2, Jinhua Wang3,4
1Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, California 94305, United States.
Journal of Medicinal Chemistry
|January 12, 2024
Summary
Novel antimalarial compounds were developed by repurposing human kinase inhibitors. Lead compound 1 targeting EphA2 was optimized to compound 33, showing improved activity against malaria.
Area of Science:
- Drug discovery and development
- Parasitology
- Medicinal chemistry
Background:
- Malaria remains a global health threat, with emerging drug resistance necessitating new treatments.
- Repurposing existing human kinase inhibitors offers a promising strategy for rapid antimalarial drug development.
- Human kinase inhibitors are a diverse class of drugs, many already approved or in clinical trials.
Purpose of the Study:
- To identify and optimize novel antimalarial agents from a library of human kinase inhibitors.
- To conduct structure-activity relationship studies on a lead antimalarial compound.
- To develop a more potent and selective antimalarial drug candidate.
Main Methods:
- Phenotypic screening of type II human kinase inhibitors.
- Identification of compound 1 (targeting human ephrin type A receptor 2 - EphA2) as a lead antimalarial.
- Structure-activity relationship (SAR) studies and lead optimization to generate compound 33.
Main Results:
- Compound 1 demonstrated initial antimalarial activity.
- Optimization efforts resulted in compound 33.
- Compound 33 exhibited enhanced antimalarial activity and selectivity compared to compound 1.
Conclusions:
- Repurposing human kinase inhibitors is a viable strategy for discovering new antimalarial drugs.
- Lead optimization of compound 1 successfully yielded compound 33 with improved efficacy.
- Further development of compound 33 holds potential for combating drug-resistant malaria.
