2. Academic Validation
  3. Discovery of Potent Antimalarial Type II Kinase Inhibitors with Selectivity over Human Kinases

Discovery of Potent Antimalarial Type II Kinase Inhibitors with Selectivity over Human Kinases

  • J Med Chem. 2024 Jan 25;67(2):1460-1480. doi: 10.1021/acs.jmedchem.3c02046.
Lushun Wang 1,  Monica J Bohmer 2,  Jinhua Wang 3 4,  Flore Nardella 2,  Jaeson Calla 5,  Mariana Laureano De Souza 5,  Kyra A Schindler 6,  Lukas Montejo 2,  Nimisha Mittal 5,  Frances Rocamora 5,  Mayland Treat 7,  Jordan T Charlton 8,  Patrick K Tumwebaze 9,  Philip J Rosenthal 10,  Roland A Cooper 8,  Ratna Chakrabarti 11,  Elizabeth A Winzeler 5,  Debopam Chakrabarti 2,  Nathanael S Gray 1
Affiliations

Affiliations

  • 1 Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, California 94305, United States.
  • 2 Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, Florida 32826, United States.
  • 3 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States.
  • 4 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 5 Department of Pediatrics, School of Medicine, University California, San Diego, La Jolla, California 92093, United States.
  • 6 Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York 10032, United States.
  • 7 School of Public Health, University of California, Berkeley California 94704, United States.
  • 8 Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, California 94901, United States.
  • 9 Infectious Disease Research Collaboration, Kampala, Uganda.
  • 10 Department of Medicine, University of California, San Francisco, California 94110, United States.
  • 11 Division of Cancer Research, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, Florida 32826, United States.
PMID: 38214254 DOI: 10.1021/acs.jmedchem.3c02046
Abstract

While progress has been made in the effort to eradicate malaria, the disease remains a significant threat to global health. Acquired resistance to frontline treatments is emerging in Africa, urging a need for the development of novel antimalarial agents. Repurposing human kinase inhibitors provides a potential expedited route given the availability of a diverse array of kinase-targeting drugs that are approved or in clinical trials. Phenotypic screening of a library of type II human kinase inhibitors identified compound 1 as a lead antimalarial, which was initially developed to target human ephrin type A receptor 2 (EphA2). Here, we report a structure-activity relationship study and lead optimization of compound 1, which led to compound 33, with improved antimalarial activity and selectivity.

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