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Here, we report that the human \u201cmammalian target of rapamycin\u201d (mTOR) inhibitor sapanisertib has potent prophylactic liver stage activity, in vitro and in vivo asexual blood stage (ABS) activity, and transmission-blocking activity against the protozoan parasite\n            <jats:italic>Plasmodium<\/jats:italic>\n            spp. Chemoproteomics studies revealed multiple potential\n            <jats:italic>Plasmodium<\/jats:italic>\n            kinase targets, and potent inhibition of\n            <jats:italic>Plasmodium<\/jats:italic>\n            phosphatidylinositol 4-kinase type III beta (PI4K\u03b2) and cyclic guanosine monophosphate\u2013dependent protein kinase (PKG) was confirmed in vitro. Conditional knockdown of PI4K\u03b2 in ABS cultures modulated parasite sensitivity to sapanisertib, and laboratory-generated\n            <jats:italic>P. falciparum<\/jats:italic>\n            sapanisertib resistance was mediated by mutations in PI4K\u03b2. Parasite metabolomic perturbation profiles associated with sapanisertib and other known PI4K\u03b2 and\/or PKG inhibitors revealed similarities and differences between chemotypes, potentially caused by sapanisertib targeting multiple parasite kinases. The multistage activity of sapanisertib and its in vivo antimalarial efficacy, coupled with potent inhibition of at least two promising drug targets, provides an opportunity to reposition this pyrazolopyrimidine for malaria.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.abo7219","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T17:58:17Z","timestamp":1666202297000},"source":"Crossref","is-referenced-by-count":48,"title":["The anticancer human mTOR inhibitor sapanisertib potently inhibits multiple\n            <i>Plasmodium<\/i>\n            kinases and life cycle stages"],"prefix":"10.1126","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4699-0428","authenticated-orcid":true,"given":"Lauren B.","family":"Arendse","sequence":"first","affiliation":[{"name":"Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch, Cape Town 7701, South Africa."},{"name":"Institute of Infectious Disease and Molecular 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