TY - JOUR
T1 - The anticancer human mTOR inhibitor sapanisertib potently inhibits multiple Plasmodium kinases and life cycle stages
AU - Arendse, Lauren B.
AU - Murithi, James M.
AU - Qahash, Tarrick
AU - Pasaje, Charisse Flerida A.
AU - Godoy, Luiz C.
AU - Dey, Sumanta
AU - Gibhard, Liezl
AU - Ghidelli-Disse, Sonja
AU - Drewes, Gerard
AU - Bantscheff, Marcus
AU - Lafuente-Monasterio, Maria J.
AU - Fienberg, Stephen
AU - Wambua, Lynn
AU - Gachuhi, Samuel
AU - Coertzen, Dina
AU - van der Watt, Mariëtte
AU - Reader, Janette
AU - Aswat, Ayesha S.
AU - Erlank, Erica
AU - Venter, Nelius
AU - Mittal, Nimisha
AU - Luth, Madeline R.
AU - Ottilie, Sabine
AU - Winzeler, Elizabeth A.
AU - Koekemoer, Lizette L.
AU - Birkholtz, Lyn Marie
AU - Niles, Jacquin C.
AU - Llinás, Manuel
AU - Fidock, David A.
AU - Chibale, Kelly
N1 - Funding Information:
This work was supported by 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 (to L.B.A.); the South African Medical Research Council (to K.C.); South African Research Chairs Initiative (SARChI) of the Department of Science and Innovation, administered through the South African National Research Foundation (SA NRF) (UID 64767 to K.C., UID 84627 to L.M.B., and UID 64763 to L.L.K.); the NRF Communities of Practice grant from SARCHI (UID 110666 to L.-M.B., L.L.K., and K.C.); the Bill and Melinda Gates Foundation that funds the Malarial Drug Accelerator (MalDA) consortium (OPP1054480 to E.A.W., D.A.F., S.O., and M.L.; OPP1162467 to J.C.N.; and OPP1066878 to K.C.), and the Ruth L. Kirschstein Institutional National Research Award from the National Institute for General Medical Sciences T32 GM008666 (to M.R.L.).
Funding Information:
Acknowledgments: W e thank the Huck Institutes of Life Sciences Metabolomics Core Fa cility at Penn State University. Funding: This work was supported by 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 (to L.B.A.); the South African Medical Research Council (to K.C.); South African Research Chairs Initiative (SARChI) of the Department of Science and Innovation, administered through the South African National Research Foundation (SA NRF) (UID 64767 to K.C., UID 84627 to L.-M.B., and UID 64763 to L.L.K.); the NRF Communities of Practice grant from SARCHI (UID 110666 to L.-M.B., L.L.K., and K.C.); the Bill and Melinda Gates Foundation that funds the Malarial Drug Accelerator (MalDA) consortium (OPP1054480 to E.A.W ., D.A.F ., S.O., and M.L.; OPP1162467 to J.C.N.; and OPP1066878 to K.C.), and the Ruth L. Kirschstein Institutional National Research A ward from the National Institute for General Medical Sciences T32 GM008666 (to M.R.L.). Author contributions: N.M. performed ABS and liver stage susceptibility testing. D.C., M.v.d.W ., and J.R. performed gametocytocidal, gamete exflagellation inhibition, and female gamete activation assays. E.E., N.V ., A.S.A., and L.L.K. performed SMFA analysis and interpretation of data. S.G. synthesized sapanisertib for in vivo NSG mouse studies. L.G. performed NSG mouse studies. S.G.-D., G.D., M.B., and M.J.L.-M. performed chemoproteomic studies. L.B.A. and L.W . performed recombinant kinase inhibition studies. C.F .A.P ., L.C.G., and S.D. performed cKD experiments. J.M.M. performed resistance selections. M.R.L. analyzed sequencing data. S.F . performed in silico docking studies. T .Q. carried out all metabolomics experiments. S.O., E.A.W ., L.L.K., L.-M.B., J.C.N., M.L., D.A.F ., and K.C. supervised individual labora tory efforts and provided expertise. L.B.A. wrote the manuscript with input from K.C., D.A.F ., and other authors. All authors approv ed the final manuscript. Competing interests: The authors declare that they hav e no competing interests. Data and materials availability: All metabolomics data are available publicly through the NCBI Metabolomics W orkbench (62) (Project ID: PR001275). All other relevant data are available in the Supplementary Materials. Requests for resources and reagents should be directed to the corresponding author.
Publisher Copyright:
Copyright © 2022 The Authors, some rights reserved.
PY - 2022/10/19
Y1 - 2022/10/19
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85140415261&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.abo7219
DO - 10.1126/scitranslmed.abo7219
M3 - Article
C2 - 36260689
AN - SCOPUS:85140415261
SN - 1946-6234
VL - 14
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 667
M1 - eabo7219
ER -