The anticancer human mTOR inhibitor sapanisertib potently inhibits multiple Plasmodium kinases and life cycle stages

Lauren B. Arendse, James M. Murithi, Tarrick Qahash, Charisse Flerida A. Pasaje, Luiz C. Godoy, Sumanta Dey, Liezl Gibhard, Sonja Ghidelli-Disse, Gerard Drewes, Marcus Bantscheff, Maria J. Lafuente-Monasterio, Stephen Fienberg, Lynn Wambua, Samuel Gachuhi, Dina Coertzen, Mariëtte van der Watt, Janette Reader, Ayesha S. Aswat, Erica Erlank, Nelius VenterNimisha Mittal, Madeline R. Luth, Sabine Ottilie, Elizabeth A. Winzeler, Lizette L. Koekemoer, Lyn Marie Birkholtz, Jacquin C. Niles, Manuel Llinás, David A. Fidock, Kelly Chibale

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Compounds acting on multiple targets are critical to combating antimalarial drug resistance. Here, we report that the human “mammalian target of rapamycin” (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 Plasmodium spp. Chemoproteomics studies revealed multiple potential Plasmodium kinase targets, and potent inhibition of Plasmodium phosphatidylinositol 4-kinase type III beta (PI4Kβ) and cyclic guanosine monophosphate–dependent protein kinase (PKG) was confirmed in vitro. Conditional knockdown of PI4Kβ in ABS cultures modulated parasite sensitivity to sapanisertib, and laboratory-generated P. falciparum sapanisertib resistance was mediated by mutations in PI4Kβ. Parasite metabolomic perturbation profiles associated with sapanisertib and other known PI4Kβ 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.

Original languageEnglish (US)
Article numbereabo7219
JournalScience Translational Medicine
Volume14
Issue number667
DOIs
StatePublished - Oct 19 2022

All Science Journal Classification (ASJC) codes

  • General Medicine

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