Medicinal chemistry progression of sapanisertib, the anticancer and dual Plasmodium phosphatidylinositol 4-kinase beta and cGMP-dependent protein kinase inhibitor, for malaria
dc.contributor.author | Gachuhi, Samuel | |
dc.contributor.author | Kamunya, Stephanie | |
dc.contributor.author | Fienberg, Stephen | |
dc.contributor.author | Wambua, Lynn | |
dc.contributor.author | Salomane, Nicolaas | |
dc.contributor.author | Mayoka, Godfrey | |
dc.contributor.author | Taylor, Dale | |
dc.contributor.author | Coertzen, Dina | |
dc.contributor.author | Van der Watt, Mariette Elizabeth | |
dc.contributor.author | Reader, Janette | |
dc.contributor.author | Birkholtz, Lyn-Marie | |
dc.contributor.author | Wittlin, Sergio | |
dc.contributor.author | Krugmann, Liezl | |
dc.contributor.author | Coulson, Lauren B. | |
dc.contributor.author | Chibale, Kelly | |
dc.date.accessioned | 2025-07-09T09:36:20Z | |
dc.date.available | 2025-07-09T09:36:20Z | |
dc.date.issued | 2025-06 | |
dc.description.abstract | We 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.department | Biochemistry, Genetics and Microbiology (BGM) | |
dc.description.department | UP Centre for Sustainable Malaria Control (UP CSMC) | |
dc.description.librarian | hj2025 | |
dc.description.sdg | SDG-03: Good health and well-being | |
dc.description.sponsorship | The 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.uri | https://pubs.acs.org/journal/jmcmar?ref=breadcrumb | |
dc.identifier.citation | Gachuhi, 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.issn | 0022-2623 (print) | |
dc.identifier.issn | 1520-4804 (online) | |
dc.identifier.other | 10.1021/acs.jmedchem.4c02799 | |
dc.identifier.uri | http://hdl.handle.net/2263/103246 | |
dc.language.iso | en | |
dc.publisher | American Chemical Society | |
dc.rights | © 2025 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY 4.0 . | |
dc.subject | Malaria | |
dc.subject | Sapanisertib | |
dc.subject | Plasmodium kinases | |
dc.subject | Phosphatidy-linositol 4-kinase type III beta (PI4Kβ) | |
dc.subject | GMP-dependent protein kinase (PKG) | |
dc.title | Medicinal chemistry progression of sapanisertib, the anticancer and dual Plasmodium phosphatidylinositol 4-kinase beta and cGMP-dependent protein kinase inhibitor, for malaria | |
dc.type | Article |
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