Open AccessTorin 2 Derivative, NCATS-SM3710, Has Potent Multistage Antimalarial Activity through Inhibition of P. falciparum Phosphatidylinositol 4-Kinase (Pf PI4KIIIβ)
Author(s) -
Karthik Krishnan,
Peter Ziniel,
Hao Li,
Xiaolin Huang,
Daniel Hupalo,
Nita Gombakomba,
Sandra Mendoza Guerrero,
Thoai Dotrang,
Xiao Lü,
Diana Caridha,
Anna R. Sternberg,
Emma Hughes,
Wei Sun,
Daniel Youssef Bargieri,
Paul D. Roepe,
Richard J Sciotti,
Matthew D. Wilkerson,
Clifton L. Dalgard,
Gregory J. Tawa,
Amy Q. Wang,
Xin Xu,
Wei Zheng,
Philip E.J. Sanderson,
Wenwei Huang,
Kim C. Williamson
Publication year - 2020
Publication title -
acs pharmacology and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.271
H-Index - 10
ISSN - 2575-9108
DOI - 10.1021/acsptsci.0c00078
Subject(s) - plasmodium falciparum , biology , gametocyte , ic50 , cancer research , in vivo , cell culture , malaria , genetics , immunology
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 EC 50 s 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 IC 50 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.