Medicinal chemistry progression of sapanisertib, the anticancer and dual Plasmodium phosphatidylinositol 4-kinase beta and cGMP-dependent protein kinase inhibitor, for malaria

dc.contributor.authorGachuhi, Samuel
dc.contributor.authorKamunya, Stephanie
dc.contributor.authorFienberg, Stephen
dc.contributor.authorWambua, Lynn
dc.contributor.authorSalomane, Nicolaas
dc.contributor.authorMayoka, Godfrey
dc.contributor.authorTaylor, Dale
dc.contributor.authorCoertzen, Dina
dc.contributor.authorVan der Watt, Mariette Elizabeth
dc.contributor.authorReader, Janette
dc.contributor.authorBirkholtz, Lyn-Marie
dc.contributor.authorWittlin, Sergio
dc.contributor.authorKrugmann, Liezl
dc.contributor.authorCoulson, Lauren B.
dc.contributor.authorChibale, Kelly
dc.date.accessioned2025-07-09T09:36:20Z
dc.date.available2025-07-09T09:36:20Z
dc.date.issued2025-06
dc.description.abstractWe recently demonstrated that the anticancer human mTOR inhibitor sapanisertib displays antimalarial activity in a malaria mouse model of infection and inhibits multiple Plasmodium kinases, including the high-value targets phosphatidylinositol 4-kinase type III beta (PI4Kβ) and cGMP-dependent protein kinase (PKG). Herein, we explore structure-activity relationships for sapanisertib analogues with benzyl and pyridyl substituents at the 7-position of the pyrazolopyrimidine core. New analogues with improved safety profiles were identified, including analogues with dual Plasmodium PI4Kβ and PKG inhibitory activity (exemplified by 19), as well as potent Plasmodium PI4Kβ inhibitors with minimal inhibitory activity against PKG (exemplified by 20). Compound 19 displayed potent antiplasmodium activity, high microsomal metabolic stability, and a good safety profile (hERG IC50 > 30; cytotoxicity selectivity index = 99). In vivo proof-of-concept, where a 4 × 50 mg kg-1 oral dose of 19 resulted in an 80% reduction in parasitemia in P. berghei-infected mice, further demonstrated the lead potential of this series. against respiratory-related infections with economic potential.
dc.description.departmentBiochemistry, Genetics and Microbiology (BGM)
dc.description.departmentUP Centre for Sustainable Malaria Control (UP CSMC)
dc.description.librarianhj2025
dc.description.sdgSDG-03: Good health and well-being
dc.description.sponsorshipThe South African Medical Research Council, and South African Research Chairs Initiative of the Department of Science and Innovation, administered through the South African National Research Foundation, Neville Isdell for the Neville Isdell Chair in African-centric Drug Discovery and Development, the Medicines for Malaria Venture, the Future Leaders–African Independent Research (FLAIR) Fellowship Programme, a partnership between the African Academy of Sciences and the Royal Society funded by the UK Government’s Global Challenges Research Fund and the University of Cape Town.
dc.description.urihttps://pubs.acs.org/journal/jmcmar?ref=breadcrumb
dc.identifier.citationGachuhi, S., Kamunya, S., Fienberg, S. et al. 2025, 'Medicinal chemistry progression of sapanisertib, the anticancer and dual Plasmodium phosphatidylinositol 4-kinase beta and cGMP-dependent protein kinase inhibitor, for malaria', Journal of Medicinal Chemistry, vol. 68, no. 11, pp. 10757-10770, doi : 10.1021/acs.jmedchem.4c02799.
dc.identifier.issn0022-2623 (print)
dc.identifier.issn1520-4804 (online)
dc.identifier.other10.1021/acs.jmedchem.4c02799
dc.identifier.urihttp://hdl.handle.net/2263/103246
dc.language.isoen
dc.publisherAmerican Chemical Society
dc.rights© 2025 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY 4.0 .
dc.subjectMalaria
dc.subjectSapanisertib
dc.subjectPlasmodium kinases
dc.subjectPhosphatidy-linositol 4-kinase type III beta (PI4Kβ)
dc.subjectGMP-dependent protein kinase (PKG)
dc.titleMedicinal chemistry progression of sapanisertib, the anticancer and dual Plasmodium phosphatidylinositol 4-kinase beta and cGMP-dependent protein kinase inhibitor, for malaria
dc.typeArticle

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