PMID- 36260689
OWN - NLM
STAT- MEDLINE
DCOM- 20221021
LR  - 20231020
IS  - 1946-6242 (Electronic)
IS  - 1946-6234 (Print)
IS  - 1946-6234 (Linking)
VI  - 14
IP  - 667
DP  - 2022 Oct 19
TI  - The anticancer human mTOR inhibitor sapanisertib potently inhibits multiple 
      Plasmodium kinases and life cycle stages.
PG  - eabo7219
LID - 10.1126/scitranslmed.abo7219 [doi]
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 (PI4Kbeta) and cyclic guanosine 
      monophosphate-dependent protein kinase (PKG) was confirmed in vitro. Conditional 
      knockdown of PI4Kbeta in ABS cultures modulated parasite sensitivity to 
      sapanisertib, and laboratory-generated P. falciparum sapanisertib resistance was 
      mediated by mutations in PI4Kbeta. Parasite metabolomic perturbation profiles 
      associated with sapanisertib and other known PI4Kbeta 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.
FAU - Arendse, Lauren B
AU  - Arendse LB
AUID- ORCID: 0000-0003-4699-0428
AD  - Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch, 
      Cape Town 7701, South Africa.
AD  - Institute of Infectious Disease and Molecular Medicine, University of Cape Town, 
      Observatory, Cape Town 7925, South Africa.
AD  - South African Medical Research Council Drug Discovery and Development Research 
      Unit, University of Cape Town, Rondebosch, Cape Town 7701, South Africa.
FAU - Murithi, James M
AU  - Murithi JM
AUID- ORCID: 0000-0003-0741-8461
AD  - Department of Microbiology and Immunology, Columbia University Irving Medical 
      Center, New York, NY 10032, USA.
FAU - Qahash, Tarrick
AU  - Qahash T
AUID- ORCID: 0000-0003-2891-3090
AD  - Department of Biochemistry and Molecular Biology, Pennsylvania State University, 
      University Park, PA 16802, USA.
AD  - Huck Center for Malaria Research, Pennsylvania State University, University Park, 
      PA 16802, USA.
FAU - Pasaje, Charisse Flerida A
AU  - Pasaje CFA
AUID- ORCID: 0000-0002-9780-3680
AD  - Department of Biological Engineering, Massachusetts Institute of Technology, 
      Cambridge, MA 02139, USA.
FAU - Godoy, Luiz C
AU  - Godoy LC
AD  - Department of Biological Engineering, Massachusetts Institute of Technology, 
      Cambridge, MA 02139, USA.
FAU - Dey, Sumanta
AU  - Dey S
AUID- ORCID: 0000-0002-5945-976X
AD  - Department of Biological Engineering, Massachusetts Institute of Technology, 
      Cambridge, MA 02139, USA.
FAU - Gibhard, Liezl
AU  - Gibhard L
AD  - Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch, 
      Cape Town 7701, South Africa.
FAU - Ghidelli-Disse, Sonja
AU  - Ghidelli-Disse S
AUID- ORCID: 0000-0002-7735-9746
AD  - Cellzome GmbH, a GSK Company, Heidelberg 69117, Germany.
FAU - Drewes, Gerard
AU  - Drewes G
AUID- ORCID: 0000-0003-0575-6766
AD  - Cellzome GmbH, a GSK Company, Heidelberg 69117, Germany.
FAU - Bantscheff, Marcus
AU  - Bantscheff M
AUID- ORCID: 0000-0002-8343-8977
AD  - Cellzome GmbH, a GSK Company, Heidelberg 69117, Germany.
FAU - Lafuente-Monasterio, Maria J
AU  - Lafuente-Monasterio MJ
AUID- ORCID: 0000-0002-4583-9649
AD  - Tres Cantos Medicines Development Campus-Diseases of the Developing World, 
      GlaxoSmithKline, Tres Cantos, Madrid 28760, Spain.
FAU - Fienberg, Stephen
AU  - Fienberg S
AUID- ORCID: 0000-0002-6228-6783
AD  - Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch, 
      Cape Town 7701, South Africa.
AD  - Department of Chemistry, University of Cape Town, Rondebosch, Cape Town 7701, 
      South Africa.
FAU - Wambua, Lynn
AU  - Wambua L
AUID- ORCID: 0000-0002-6218-199X
AD  - Institute of Infectious Disease and Molecular Medicine, University of Cape Town, 
      Observatory, Cape Town 7925, South Africa.
AD  - Department of Chemistry, University of Cape Town, Rondebosch, Cape Town 7701, 
      South Africa.
FAU - Gachuhi, Samuel
AU  - Gachuhi S
AUID- ORCID: 0000-0002-3907-5179
AD  - Department of Chemistry, University of Cape Town, Rondebosch, Cape Town 7701, 
      South Africa.
FAU - Coertzen, Dina
AU  - Coertzen D
AUID- ORCID: 0000-0002-8408-244X
AD  - Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable 
      Malaria Control, University of Pretoria, Hatfield 0028, South Africa.
FAU - van der Watt, Mariette
AU  - van der Watt M
AUID- ORCID: 0000-0002-9933-8647
AD  - Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable 
      Malaria Control, University of Pretoria, Hatfield 0028, South Africa.
FAU - Reader, Janette
AU  - Reader J
AUID- ORCID: 0000-0001-9026-0583
AD  - Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable 
      Malaria Control, University of Pretoria, Hatfield 0028, South Africa.
FAU - Aswat, Ayesha S
AU  - Aswat AS
AUID- ORCID: 0000-0002-5326-6764
AD  - Wits Research Institute for Malaria, School of Pathology, Faculty of Health 
      Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa.
AD  - Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for 
      Communicable Diseases of the National Health Laboratory Service, Johannesburg 
      2193, South Africa.
FAU - Erlank, Erica
AU  - Erlank E
AUID- ORCID: 0000-0002-9687-6095
AD  - Wits Research Institute for Malaria, School of Pathology, Faculty of Health 
      Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa.
AD  - Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for 
      Communicable Diseases of the National Health Laboratory Service, Johannesburg 
      2193, South Africa.
FAU - Venter, Nelius
AU  - Venter N
AD  - Wits Research Institute for Malaria, School of Pathology, Faculty of Health 
      Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa.
AD  - Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for 
      Communicable Diseases of the National Health Laboratory Service, Johannesburg 
      2193, South Africa.
FAU - Mittal, Nimisha
AU  - Mittal N
AUID- ORCID: 0000-0002-4810-9334
AD  - School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
FAU - Luth, Madeline R
AU  - Luth MR
AUID- ORCID: 0000-0001-9059-1200
AD  - School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
FAU - Ottilie, Sabine
AU  - Ottilie S
AUID- ORCID: 0000-0001-9797-2612
AD  - School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
FAU - Winzeler, Elizabeth A
AU  - Winzeler EA
AD  - School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
FAU - Koekemoer, Lizette L
AU  - Koekemoer LL
AUID- ORCID: 0000-0003-4236-6345
AD  - Wits Research Institute for Malaria, School of Pathology, Faculty of Health 
      Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa.
AD  - Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for 
      Communicable Diseases of the National Health Laboratory Service, Johannesburg 
      2193, South Africa.
FAU - Birkholtz, Lyn-Marie
AU  - Birkholtz LM
AUID- ORCID: 0000-0001-5888-2905
AD  - Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable 
      Malaria Control, University of Pretoria, Hatfield 0028, South Africa.
FAU - Niles, Jacquin C
AU  - Niles JC
AUID- ORCID: 0000-0002-6250-8796
AD  - Department of Biological Engineering, Massachusetts Institute of Technology, 
      Cambridge, MA 02139, USA.
FAU - Llinas, Manuel
AU  - Llinas M
AUID- ORCID: 0000-0002-6173-5882
AD  - Department of Biochemistry and Molecular Biology, Pennsylvania State University, 
      University Park, PA 16802, USA.
AD  - Huck Center for Malaria Research, Pennsylvania State University, University Park, 
      PA 16802, USA.
AD  - Department of Chemistry, Pennsylvania State University, University Park, PA 
      16802, USA.
FAU - Fidock, David A
AU  - Fidock DA
AUID- ORCID: 0000-0001-6753-8938
AD  - Department of Microbiology and Immunology, Columbia University Irving Medical 
      Center, New York, NY 10032, USA.
AD  - Center for Malaria Therapeutics and Antimicrobial Resistance, Division of 
      Infectious Diseases, Columbia University Irving Medical Center, New York, NY 
      10032, USA.
FAU - Chibale, Kelly
AU  - Chibale K
AUID- ORCID: 0000-0002-4541-646X
AD  - Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch, 
      Cape Town 7701, South Africa.
AD  - Institute of Infectious Disease and Molecular Medicine, University of Cape Town, 
      Observatory, Cape Town 7925, South Africa.
AD  - South African Medical Research Council Drug Discovery and Development Research 
      Unit, University of Cape Town, Rondebosch, Cape Town 7701, South Africa.
AD  - Department of Chemistry, University of Cape Town, Rondebosch, Cape Town 7701, 
      South Africa.
LA  - eng
GR  - T32 GM008666/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20221019
PL  - United States
TA  - Sci Transl Med
JT  - Science translational medicine
JID - 101505086
RN  - 0 (Antimalarials)
RN  - JGH0DF1U03 (sapanisertib)
RN  - 0 (MTOR Inhibitors)
RN  - EC 2.7.1.67 (1-Phosphatidylinositol 4-Kinase)
RN  - 85-32-5 (Guanosine Monophosphate)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
SB  - IM
MH  - Animals
MH  - Humans
MH  - *Antimalarials/pharmacology/therapeutic use
MH  - Plasmodium falciparum
MH  - MTOR Inhibitors
MH  - 1-Phosphatidylinositol 4-Kinase
MH  - Guanosine Monophosphate
MH  - Life Cycle Stages
MH  - TOR Serine-Threonine Kinases
MH  - *Plasmodium
MH  - Sirolimus
MH  - Mammals
PMC - PMC9951552
MID - NIHMS1865100
COIS- Competing interests: The authors declare that they have no competing interests.
EDAT- 2022/10/20 06:00
MHDA- 2022/10/22 06:00
PMCR- 2023/10/19
CRDT- 2022/10/19 14:03
PHST- 2022/10/19 14:03 [entrez]
PHST- 2022/10/20 06:00 [pubmed]
PHST- 2022/10/22 06:00 [medline]
PHST- 2023/10/19 00:00 [pmc-release]
AID - 10.1126/scitranslmed.abo7219 [doi]
PST - ppublish
SO  - Sci Transl Med. 2022 Oct 19;14(667):eabo7219. doi: 10.1126/scitranslmed.abo7219. 
      Epub 2022 Oct 19.