NDLI: Torin 2 Derivative, NCATS-SM3710, Has Potent Multistage Antimalarial Activity through Inhibition of <i>P. falciparum</i> Phosphatidylinositol 4-Kinase (<i>Pf</i> PI4KIIIβ).

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Torin 2 Derivative, NCATS-SM3710, Has Potent Multistage Antimalarial Activity through Inhibition of P. falciparum Phosphatidylinositol 4-Kinase (Pf PI4KIIIβ).

Content Provider	Europe PMC
Author	Krishnan, Karthik Ziniel, Peter Li, Hao Huang, Xiuli Hupalo, Daniel Gombakomba, Nita Guerrero, Sandra Mendoza Dotrang, Thoai Lu, Xiao Caridha, Diana Sternberg, Anna R. Hughes, Emma Sun, Wei Bargieri, Daniel Y. Roepe, Paul D. Sciotti, Richard J. Wilkerson, Matthew D. Dalgard, Clifton L. Tawa, Gregory J. Wang, Amy Q. Xu, Xin Zheng, Wei Sanderson, Philip E. Huang, Wenwei Williamson, Kim C.
Copyright Year	2020
Description	Drug resistance is a constant threat to malaria control efforts making it important to maintain a good pipeline of new drug candidates. Of particular need are compounds that also block transmission by targeting sexual stage parasites. Mature sexual stages are relatively resistant to all currently used antimalarials except the 8-aminoquinolines that are not commonly used due to potential side effects. Here, we synthesized a new Torin 2 derivative, NCATS-SM3710 with increased aqueous solubility and specificity for Plasmodium and demonstrate potent in vivo activity against all P. berghei life cycle stages. NCATS-SM3710 also has low nanomolar EC50s against in vitro cultured asexual P. falciparum parasites (0.38 ± 0.04 nM) and late stage gametocytes (5.77 ± 1 nM). Two independent NCATS-SM3710/Torin 2 resistant P. falciparum parasite lines produced by growth in sublethal Torin 2 concentrations both had genetic changes in PF3D7_0509800, annotated as a phosphatidylinositol 4 kinase (Pf PI4KIIIβ). One line had a point mutation in the putative active site (V1357G), and the other line had a duplication of a locus containing Pf PI4KIIIβ. Both lines were also resistant to other Pf PI4K inhibitors. In addition NCATS-SM3710 inhibited purified Pf PI4KIIIβ with an IC50 of 2.0 ± 0.30 nM. Together the results demonstrate that Pf PI4KIIIβ is the target of Torin 2 and NCATS-SM3710 and provide new options for potent multistage drug development.
Abstract	Drug resistance is a constant threatto malaria control effortsmaking it important to maintain a good pipeline of new drug candidates.Of particular need are compounds that also block transmission by targetingsexual stage parasites. Mature sexual stages are relatively resistantto all currently used antimalarials except the 8-aminoquinolines thatare not commonly used due to potential side effects. Here, we synthesizeda new Torin 2 derivative, NCATS-SM3710 with increased aqueous solubilityand specificity for Plasmodium and demonstrate potent in vivo activity against all P. berghei life cycle stages. NCATS-SM3710 also has low nanomolar EC50s against in vitro cultured asexual P. falciparum parasites (0.38 ± 0.04 nM) and late stage gametocytes (5.77± 1 nM). Two independent NCATS-SM3710/Torin 2 resistant P. falciparum parasite lines produced by growth in sublethalTorin 2 concentrations both had genetic changes in PF3D7_0509800,annotated as a phosphatidylinositol 4 kinase (Pf PI4KIIIβ).One line had a point mutation in the putative active site (V1357G),and the other line had a duplication of a locus containing Pf PI4KIIIβ. Both lines were also resistantto other Pf PI4K inhibitors. In addition NCATS-SM3710inhibited purified Pf PI4KIIIβ withan IC50 of 2.0 ± 0.30 nM. Together the results demonstratethat Pf PI4KIIIβ is the target of Torin2 and NCATS-SM3710 and provide new options for potent multistage drugdevelopment.
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC7551716&blobtype=pdf
Volume Number	3
DOI	10.1021/acsptsci.0c00078
PubMed Central reference number	PMC7551716
Issue Number	5
PubMed reference number	33073193
Journal	ACS Pharmacology & Translational Science [ACS Pharmacol Transl Sci]
e-ISSN	25759108
Language	English
Publisher	American Chemical Society
Publisher Date	2020-09-11
Access Restriction	Open
Subject Keyword	Plasmodium falciparum malaria drug discovery transmission-blocking PI4K drug resistance
Content Type	Text
Resource Type	Article
Subject	Pharmacology (medical) Pharmacology

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Torin 2 Derivative, NCATS-SM3710, Has Potent Multistage Antimalarial Activity through Inhibition of P. falciparum Phosphatidylinositol 4-Kinase (Pf PI4KIIIβ).

Torin 2 Derivative, NCATS-SM3710, Has Potent Multistage Antimalarial Activity through Inhibition of P. falciparum Phosphatidylinositol 4-Kinase (Pf PI4KIIIβ).