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

  • Journal Article

Journal:
Science translational medicine, Volume: 14, Issue: 667
Published:
October 19, 2022
PMID:
36260689
Authors:
Lauren B Arendse LB, James M Murithi JM, Tarrick Qahash T, Charisse Flerida A Pasaje CFA, Luiz C Godoy LC, Sumanta Dey S, Liezl Gibhard L, Sonja Ghidelli-Disse S, Gerard Drewes G, Marcus Bantscheff M, Maria J Lafuente-Monasterio MJ, Stephen Fienberg S, Lynn Wambua L, Samuel Gachuhi S, Dina Coertzen D, Mariëtte van der Watt M, Janette Reader J, Ayesha S Aswat AS, Erica Erlank E, Nelius Venter N, Nimisha Mittal N, Madeline R Luth MR, Sabine Ottilie S, Elizabeth A Winzeler EA, Lizette L Koekemoer LL, Lyn-Marie Birkholtz LM, Jacquin C Niles JC, Manuel Llinás M, David A Fidock DA, Kelly Chibale K
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 spp. Chemoproteomics studies revealed multiple potential kinase targets, and potent inhibition of 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 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.