Torin 2 Derivative, NCATS-SM3710, Has Potent Multistage Antimalarial Activity through Inhibition of P. falciparum Phosphatidylinositol 4-Kinase (PfâPI4KIIIβ)

Karthik Krishnan, Peter Ziniel, Hao Li, Xiuli Huang, Daniel Hupalo, Nita Gombakomba, Sandra Mendoza Guerrero, Thoai Dotrang, Xiao Lu, Diana Caridha, Anna R. Sternberg, Emma Hughes, Wei Sun, Daniel Y. Bargieri, Paul D. Roepe, Richard J. Sciotti, Matthew D. Wilkerson, Clifton L. Dalgard, Gregory J. Tawa, Amy Q. WangXin Xu, Wei Zheng, Philip E. Sanderson, Wenwei Huang, Kim C. Williamson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

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 (PfâPI4KIIIβ). One line had a point mutation in the putative active site (V1357G), and the other line had a duplication of a locus containing PfâPI4KIIIβ. Both lines were also resistant to other PfâPI4K inhibitors. In addition NCATS-SM3710 inhibited purified PfâPI4KIIIβ with an IC50 of 2.0 ± 0.30 nM. Together the results demonstrate that PfâPI4KIIIβ is the target of Torin 2 and NCATS-SM3710 and provide new options for potent multistage drug development.

Original languageEnglish
Pages (from-to)948-964
Number of pages17
JournalACS Pharmacology and Translational Science
Volume3
Issue number5
DOIs
StatePublished - 9 Oct 2020
Externally publishedYes

Keywords

  • PI4K
  • Plasmodium falciparum
  • drug discovery
  • drug resistance
  • malaria
  • transmission-blocking

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