ArticleAntimicrobial agents and chemotherapy2015
Imidazopyridazine Inhibitors of Plasmodium falciparum Calcium-Dependent Protein Kinase 1 Also Target Cyclic GMP-Dependent Protein Kinase and Heat Shock Protein 90 To Kill the Parasite at Different Stages of Intracellular Development.
Article in Antimicrobial agents and chemotherapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 57 citations in OpenAlex.
- Unveiling the impact of cGMP-dependent protein kinase of Neospora caninum on calcium fluxes and egress functions through quantitative phosphoproteome analysis.Communications biology · 2025Article
- In silico prediction and in vitro assessment of novel heterocyclics with antimalarial activity.Parasitology research · 2023Article
- Chemo-proteomics in antimalarial target identification and engagement.Medicinal research reviews · 2023Review
- Structural Basis of Parasitic HSP90 ATPase Inhibition by Small Molecules.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Targeting theHeliyon · 2022Review
- Imidazopyridazine Acetylcholinesterase Inhibitors Display Potent Anti-Proliferative Effects in the Human Neuroblastoma Cell-Line, IMR-32.Molecules (Basel, Switzerland) · 2021Article
- Review
- CaScience advances · 2021Article
- Calcium in the Backstage of Malaria Parasite Biology.Frontiers in cellular and infection microbiology · 2021Review
- cAMP-Dependent Signaling Pathways as Potential Targets for Inhibition ofFrontiers in microbiology · 2021Review
- CDPKs: The critical decoders of calcium signal at various stages of malaria parasite development.Computational and structural biotechnology journal · 2021Review
- An Update on Development of Small-Molecule Plasmodial Kinase Inhibitors.Molecules (Basel, Switzerland) · 2020Review
- Heat Shock Protein 90 (Hsp90)-Inhibitor-Luminespib-Loaded-Protein-Based Nanoformulation for Cancer Therapy.Polymers · 2020Article
- Inhibition of Resistance-Refractory P. falciparum Kinase PKG Delivers Prophylactic, Blood Stage, and Transmission-Blocking Antiplasmodial Activity.Cell chemical biology · 2020Article
- Ubiquitin activation is essential for schizont maturation in Plasmodium falciparum blood-stage development.PLoS pathogens · 2020Article
- Malaria and tuberculosis as diseases of neglected populations: state of the art in chemotherapy and advances in the search for new drugs.Memorias do Instituto Oswaldo Cruz · 2020Review
- Targeting the Malaria Parasite cGMP-Dependent Protein Kinase to Develop New Drugs.Frontiers in microbiology · 2020Review
- Partners in Mischief: Functional Networks of Heat Shock Proteins ofBiomolecules · 2019Review
- Structure-Guided Identification of Resistance Breaking Antimalarial N‑Myristoyltransferase Inhibitors.Cell chemical biology · 2019Article
- High-throughput screening of the Plasmodium falciparum cGMP-dependent protein kinase identified a thiazole scaffold which kills erythrocytic and sexual stage parasites.Scientific reports · 2019Article
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Authors and funding
17 authors at 4 institutions in 2 countries.
Funding
Abstract
Imidazopyridazine compounds are potent, ATP-competitive inhibitors of calcium-dependent protein kinase 1 (CDPK1) and of Plasmodium falciparum parasite growth in vitro. Here, we show that these compounds can be divided into two classes depending on the nature of the aromatic linker between the core and the R2 substituent group. Class 1 compounds have a pyrimidine linker and inhibit parasite growth at late schizogony, whereas class 2 compounds have a nonpyrimidine linker and inhibit growth in the trophozoite stage, indicating different modes of action for the two classes. The compounds also inhibited cyclic GMP (cGMP)-dependent protein kinase (PKG), and their potency against this enzyme was greatly reduced by substitution of the enzyme's gatekeeper residue at the ATP binding site. The effectiveness of the class 1 compounds against a parasite line expressing the modified PKG was also substantially reduced, suggesting that these compounds kill the parasite primarily through inhibition of PKG rather than CDPK1. HSP90 was identified as a binding partner of class 2 compounds, and a representative compound bound to the ATP binding site in the N-terminal domain of HSP90. Reducing the size of the gatekeeper residue of CDPK1 enabled inhibition of the enzyme by bumped kinase inhibitors; however, a parasite line expressing the modified enzyme showed no change in sensitivity to these compounds. Taken together, these findings suggest that CDPK1 may not be a suitable target for further inhibitor development and that the primary mechanism through which the imidazopyridazines kill parasites is by inhibition of PKG or HSP90.
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