Top ▲

Plasmodium falciparum phosphatidylinositol 4-kinase

Click here for help

Target not currently curated in GtoImmuPdb

Malaria Pharmacology Ligand  Target has curated data in GtoMPdb

Target id: 2972

Nomenclature: Plasmodium falciparum phosphatidylinositol 4-kinase

Abbreviated Name: PfPI4K

Family: Kinases (Plasmodium spp.)

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Plasmodium falciparum 3D7 - 1559 PI4K phosphatidylinositol 4-kinase
Database Links Click here for help
PlasmoDB
UniProtKB

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CHMFL-PI4K-127 Small molecule or natural product Pf Inhibition 9.1 pIC50 3
pIC50 9.1 (IC50 9x10-10 M) [3]
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
MMV048 Small molecule or natural product Pf Binding 6.5 – 7.0 pKd 5
pKd 7.0 (Kd 1x10-7 M) [5]
pKd 6.5 (Kd 3x10-7 M) [5]
MMV024101 Small molecule or natural product Pf3D7 - 6.2 pIC50 2
pIC50 6.2 (IC50 6x10-7 M) [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Whole Organism Assay Data Linked to This Target
Key to terms and symbols Click column headers to sort
Ligand Sp. Assay description Type Action Value Parameter Reference
CHMFL-PI4K-127 Small molecule or natural product Pf3D7 Parasite growth inhibition assay - - 7.6 pEC50 3
pEC50 7.6 (EC50 2.51x10-8 M) SYBR Green I assay [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
CHMFL-PI4K-127 Small molecule or natural product PfDd2 Parasite growth inhibition assay - - 7.5 pEC50 3
pEC50 7.5 (EC50 3.03x10-8 M) SYBR Green I assay [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
UCT943 Small molecule or natural product Pb Parasite liver stage assay - - 9.0 pIC50 1
pIC50 9.0 (IC50 9.2x10-10 M) Luciferase bioluminescence assay to measure sporozoite invasion (prophylactic activity) [1]
Lifecycle stages: Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite)
UCT943 Small molecule or natural product PfHB3 Parasite growth inhibition assay - - 8.4 pIC50 1
pIC50 8.4 (IC50 3.7x10-9 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
UCT943 Small molecule or natural product Pf7G8 Parasite growth inhibition assay - - 8.4 pIC50 1
pIC50 8.4 (IC50 4.1x10-9 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
UCT943 Small molecule or natural product PfV1/S Parasite growth inhibition assay - - 8.4 pIC50 1
pIC50 8.4 (IC50 4.2x10-9 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
UCT943 Small molecule or natural product PfK1 Parasite growth inhibition assay - - 8.3 pIC50 1
pIC50 8.3 (IC50 4.7x10-9 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
UCT943 Small molecule or natural product PfD6 Parasite growth inhibition assay - - 8.3 pIC50 1
pIC50 8.3 (IC50 5.2x10-9 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
UCT943 Small molecule or natural product PfNF54 Parasite growth inhibition assay - - 8.3 pIC50 1
pIC50 8.3 (IC50 5.4x10-9 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
UCT943 Small molecule or natural product PfDd2 Parasite growth inhibition assay - - 8.2 pIC50 1
pIC50 8.2 (IC50 5.7x10-9 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
UCT943 Small molecule or natural product Pc Parasite liver stage assay - - >8.0 pIC50 1
pIC50 >8.0 (IC50 <1x10-8 M) P. cynomolgi assay to assess inhibition of liver stage development (prophylactic activity) [1]
Lifecycle stages: Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite)
MMV048 Small molecule or natural product PfNF54 Parasite growth inhibition assay - - 7.6 pIC50 5
pIC50 7.6 (IC50 2.8x10-8 M) [3H]-hypoxanthine incorporation assay [5]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
compound 55 [PMID: 29889526] Small molecule or natural product PfNF54 - - 7.2 pIC50 2
pIC50 7.2 (IC50 6.3x10-8 M) [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
UCT943 Small molecule or natural product Pf Parasite dual gamete formation assay (DGFA) - - 7.1 pIC50 1
pIC50 7.1 (IC50 8x10-8 M) Reports on the functional viability of male and female mature stage V gametocytes [1]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
UCT943 Small molecule or natural product Pf Parasite gametocyte viability assay - - 6.9 – 7.2 pIC50 1
pIC50 7.2 (IC50 6.6x10-8 M) Parasite late stage (IV-V) gametocyte assay using luciferase reporter line [1]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
pIC50 6.9 (IC50 1.34x10-7 M) Parasite early stage (I-III) gametocyte assay using luciferase reporter line [1]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
UCT943 Small molecule or natural product Pf Standard membrane feeding assay (SMFA) - - 7.0 pIC50
pIC50 7.0 (IC50 9.6x10-8 M)
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
compound 55 [PMID: 29889526] Small molecule or natural product PfK1 - - 7.0 pIC50 2
pIC50 7.0 (IC50 1.02x10-7 M) [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
MMV048 Small molecule or natural product Pf Standard membrane feeding assay (SMFA) - - 6.9 pIC50 5
pIC50 6.9 (IC50 1.11x10-7 M) Indirect SMFA [5]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
MMV048 Small molecule or natural product PfNF54 Parasite gametocyte viability assay - - 6.6 – 6.8 pIC50 5
pIC50 6.8 (IC50 1.4x10-7 M) Parasite late stage (IV-V) gametocyte assay using luciferase reporter line [5]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
pIC50 6.7 (IC50 2.14x10-7 M) Parasite early stage (I-III) gametocyte assay using luciferase reporter line [5]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
pIC50 6.6 (IC50 2.85x10-7 M) Parasite late stage (IV-V) gametocyte assay: parasitic lactate dehydrogenase (pLDH) assay [5]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
MMV024101 Small molecule or natural product PfNF54 - - 6.3 pIC50 2
pIC50 6.3 (IC50 5.43x10-7 M) [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
MMV048 Small molecule or natural product Pc Parasite liver stage assay - - <5.0 – 7.2 pIC50 5
pIC50 7.2 (IC50 6.1x10-8 M) P. cynomolgi assay to assess inhibition of liver stage development (prophylactic activity) [5]
Lifecycle stages: Plasmodium dormant liver stage (hypnozoite)
pIC50 7.2 (IC50 6.4x10-8 M) P. cynomolgi assay to assess inhibition of liver stage development (prophylactic activity) [5]
Lifecycle stages: Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite)
pIC50 <5.0 (IC50 >1x10-5 M) P. cynomolgi assay to assess elimination of hypnozoites (potential as a radical cure) [5]
Lifecycle stages: Plasmodium dormant liver stage (hypnozoite)
Malaria Pharmacology Comments
The Plasmodium lipid kinase, phosphatidylinositol-4 kinase (PfPI4K), was first identified as the target of the imidazopyrazines, a novel class of experimental antimalarial compounds that have been shown to be active in multiple Plasmodium spp. and at each stage of malaria infection in the vertebrate host [4]. This study also reported that the imidazopyrazines act through inhibitory interaction with the ATP-binding pocket of the kinase and proposed that PfPI4K acts at the Golgi to regulate essential membrane trafficking events.

References

Show »

1. Brunschwig C, Lawrence N, Taylor D, Abay E, Njoroge M, Basarab GS, Le Manach C, Paquet T, Cabrera DG, Nchinda AT et al.. (2018) UCT943, a Next-Generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria. Antimicrob Agents Chemother, 62 (9). [PMID:29941635]

2. Kandepedu N, Gonzàlez Cabrera D, Eedubilli S, Taylor D, Brunschwig C, Gibhard L, Njoroge M, Lawrence N, Paquet T, Eyermann CJ et al.. (2018) Identification, Characterization, and Optimization of 2,8-Disubstituted-1,5-naphthyridines as Novel Plasmodium falciparum Phosphatidylinositol-4-kinase Inhibitors with in Vivo Efficacy in a Humanized Mouse Model of Malaria. J Med Chem, 61 (13): 5692-5703. [PMID:29889526]

3. Liang X, Jiang Z, Huang Z, Li F, Chen C, Hu C, Wang W, Hu Z, Liu Q, Wang B et al.. (2020) Discovery of 6'-chloro-N-methyl-5'-(phenylsulfonamido)-[3,3'-bipyridine]-5-carboxamide (CHMFL-PI4K-127) as a novel Plasmodium falciparum PI(4)K inhibitor with potent antimalarial activity against both blood and liver stages of Plasmodium. Eur J Med Chem, 188: 112012. [PMID:31911293]

4. McNamara CW, Lee MC, Lim CS, Lim SH, Roland J, Simon O, Yeung BK, Chatterjee AK, McCormack SL, Manary MJ et al.. (2013) Targeting Plasmodium PI(4)K to eliminate malaria. Nature, 504 (7479): 248-253. [PMID:24284631]

5. Paquet T, Le Manach C, Cabrera DG, Younis Y, Henrich PP, Abraham TS, Lee MCS, Basak R, Ghidelli-Disse S, Lafuente-Monasterio MJ et al.. (2017) Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase. Sci Transl Med, 9 (387). [PMID:28446690]

How to cite this page

Kinases (Plasmodium spp.): Plasmodium falciparum phosphatidylinositol 4-kinase. Last modified on 18/11/2020. Accessed on 22/06/2021. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2972.