2. Academic Validation
  3. Plasmodiumfalciparum protein kinase 6 and hemozoin formation are inhibited by a type II human kinase inhibitor exhibiting antimalarial activity

Plasmodiumfalciparum protein kinase 6 and hemozoin formation are inhibited by a type II human kinase inhibitor exhibiting antimalarial activity

  • Cell Chem Biol. 2025 Jul 17;32(7):926-941.e23. doi: 10.1016/j.chembiol.2025.06.003.
Flore Nardella 1,  Tiantian Jiang 2,  Lushun Wang 3,  Monica J Bohmer 1,  Subhoja Chakraborty 1,  John Okombo 4,  Jaeson Calla 2,  Tatiane Macedo Silva 5,  Samuel Pazicky 6,  Jianwei Che 7,  Jin Jeon 4,  Evie Vincent 1,  Nonlawat Boonyalai 8,  Rachael Coyle 8,  Mairi J Buchanan 8,  Samuel Schaefer 2,  Daisy Chen 2,  Amaan Khan 2,  Emily Mayville 4,  Mariana Laureano De Souza 2,  Mayland Treat 9,  Jordan Charlton 10,  Patrick K Tumwebaze 11,  Seth Tjia 6,  Lukas Montejo 1,  Karen Cover 1,  Philip J Rosenthal 12,  Roland A Cooper 10,  Zbynek Bozdech 6,  Marcus C S Lee 8,  Ratna Chakrabarti 1,  Sanjay A Desai 5,  David A Fidock 4,  Jinhua Wang 7,  Nathanael S Gray 13,  Elizabeth A Winzeler 14,  Debopam Chakrabarti 15
Affiliations

Affiliations

  • 1 Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL 32826, USA.
  • 2 School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences, University California, San Diego, La Jolla, CA 92093, USA.
  • 3 Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, CA 94305, USA.
  • 4 Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA; Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 5 Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
  • 6 School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
  • 7 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 8 Biological Chemistry and Drug Discovery, Wellcome Centre for Anti-Infectives Research, University of Dundee, Dundee, UK.
  • 9 School of Public Health, University of California, Berkeley CA 94704, USA.
  • 10 Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, CA 94901, USA.
  • 11 Infectious Disease Research Collaboration, Kampala, Uganda.
  • 12 Department of Medicine, University of California, San Francisco, CA 94110, USA.
  • 13 Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: nsgray01@stanford.edu.
  • 14 School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences, University California, San Diego, La Jolla, CA 92093, USA. Electronic address: ewinzeler@health.ucsd.edu.
  • 15 Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL 32826, USA. Electronic address: dchak@ucf.edu.
PMID: 40628257 DOI: 10.1016/j.chembiol.2025.06.003
Abstract

Kinase inhibitors are potent therapeutics, but most essential Plasmodium kinases remain unexploited as antimalarial targets. We identified compound 12, a type II kinase inhibitor based on aminopyridine and 2,6-benzimidazole scaffolds, as a lead compound with nanomolar potency, fast action, and in vivo activity in the Plasmodium berghei rodent malaria model. Three-hybrid luciferase fragment complementation, enzymatic studies, and cellular thermal shift assays implicated Plasmodium protein kinase 6 (PfPK6) as the target. However, conditional knockdown of PfPK6 did not alter 12 potency, suggesting complex mechanisms of action. In vitro selection for compound 12 resistance revealed mutations in three transporters: multidrug-resistance protein 1, chloroquine resistance transporter and V-type ATPase, indicating a digestive vacuole site of action. Compound 12 inhibited β-hematin and hemozoin formation while increasing free heme levels, suggesting antimalarial activity via blockade of heme detoxification. Our studies repurpose a safe human kinase inhibitor as a potent, fast-acting antimalarial with established in vivo efficacy.

Keywords

P. falciparum chloroquine resistance transporter; P. falciparum protein kinase 6; PfCRT; PfPK6; Plasmodium; hemozoin formation; malaria; type-II kinase inhibitor.

Figures
Products