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Updated: Jul 25, 2025
Author Spotlight: Identifying Compensatory Pathways in Malaria Parasites Containing Hypomorphic Allele of Essential Protein Kinases
Published on: November 22, 2024
Developing kinase inhibitors for malaria: an opportunity or liability?
Koketso S P Mogwera1, Kelly Chibale1, Lauren B Arendse1
1Drug Discovery and Development Centre (H3D), South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.
Protein and phosphoinositide kinases are key drug targets. While challenges like resistance exist, Plasmodium kinase inhibitors show promise for malaria treatment, with polypharmacology offering a strategy to mitigate resistance risks.
Area of Science:
- Biochemistry and Pharmacology
- Drug Discovery and Development
Background:
- Protein and phosphoinositide kinases are essential and druggable targets for various diseases.
- Kinase inhibitors have shown success in oncology but face challenges in selectivity and acquired resistance.
- The phosphatidylinositol 4-kinase beta inhibitor MMV390048 demonstrated efficacy in Phase 2a clinical trials for malaria.
Purpose of the Study:
- To highlight the therapeutic potential of Plasmodium kinase inhibitors for infectious diseases, particularly malaria.
- To address the challenges of selectivity and resistance in kinase drug discovery.
- To propose designed polypharmacology as a strategy to overcome resistance.
Main Methods:
- Review of existing literature on kinase inhibitors and their application in infectious diseases.
- Analysis of the potential benefits versus risks of Plasmodium kinase inhibitors.
- Exploration of polypharmacology as a drug design approach.
Main Results:
- Plasmodium kinase inhibitors present a significant opportunity for malaria treatment.
- Designed polypharmacology can potentially reduce the risk of acquired resistance.
- The efficacy of MMV390048 in clinical trials supports the viability of this approach.
Conclusions:
- The benefits of targeting Plasmodium kinases for malaria treatment likely outweigh the associated risks.
- Designed polypharmacology is a promising strategy to enhance the durability of kinase inhibitor therapies.
- Further research into Plasmodium kinase inhibitors and polypharmacology is warranted.
