title: Biochemical and antiparasitic properties of inhibitors of the Plasmodium falciparum calcium-dependent protein kinase PfCDPK1.
abstract: PfCDPK1 is a Plasmodium falciparum calcium-dependent protein kinase, which has been identified as a potential target for novel antimalarial chemotherapeutics. In order to further investigate the role of PfCDPK1, we established a high-throughput in vitro biochemical assay and used it to screen a library of over 35,000 small molecules. Five chemical series of inhibitors were initially identified from the screen, from which series 1 and 2 were selected for chemical optimization. Indicative of their mechanism of action, enzyme inhibition by these compounds was found to be sensitive to both the ATP concentration and substitution of the amino acid residue present at the "gatekeeper" position at the ATP-binding site of the enzyme. Medicinal chemistry efforts led to a series of PfCDPK1 inhibitors with 50% inhibitory concentrations (IC50s) below 10 nM against PfCDPK1 in a biochemical assay and 50% effective concentrations (EC50s) less than 100 nM for inhibition of parasite growth in vitro. Potent inhibition was combined with acceptable absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties and equipotent inhibition of Plasmodium vivax CDPK1. However, we were unable to correlate biochemical inhibition with parasite growth inhibition for this series overall. Inhibition of Plasmodium berghei CDPK1 correlated well with PfCDPK1 inhibition, enabling progression of a set of compounds to in vivo evaluation in the P. berghei rodent model for malaria. These chemical series have potential for further development as inhibitors of CDPK1.
authors: MRC Technology, Centre for Therapeutics Discovery, Mill Hill, London, United Kingdom.
authors: Keith H
authors: KH
authors: Ansell
authors: MRC Technology, Centre for Therapeutics Discovery, Mill Hill, London, United Kingdom.
authors: Hayley M
authors: HM
authors: Jones
authors: MRC Technology, Centre for Therapeutics Discovery, Mill Hill, London, United Kingdom.
authors: David
authors: D
authors: Whalley
authors: MRC Technology, Centre for Therapeutics Discovery, Mill Hill, London, United Kingdom.
authors: Alisdair
authors: A
authors: Hearn
authors: MRC Technology, Centre for Therapeutics Discovery, Mill Hill, London, United Kingdom.
authors: Debra L
authors: DL
authors: Taylor
authors: MRC Technology, Centre for Therapeutics Discovery, Mill Hill, London, United Kingdom.
authors: Emmanuel C
authors: EC
authors: Patin
authors: MRC Technology, Centre for Therapeutics Discovery, Mill Hill, London, United Kingdom.
authors: Timothy M
authors: TM
authors: Chapman
authors: MRC Technology, Centre for Therapeutics Discovery, Mill Hill, London, United Kingdom.
authors: Simon A
authors: SA
authors: Osborne
authors: MRC Technology, Centre for Therapeutics Discovery, Mill Hill, London, United Kingdom.
authors: Claire
authors: C
authors: Wallace
authors: MRC Technology, Centre for Therapeutics Discovery, Mill Hill, London, United Kingdom.
authors: Kristian
authors: K
authors: Birchall
authors: MRC Technology, Centre for Therapeutics Discovery, Mill Hill, London, United Kingdom.
authors: Jonathan
authors: J
authors: Large
authors: MRC Technology, Centre for Therapeutics Discovery, Mill Hill, London, United Kingdom.
authors: Nathalie
authors: N
authors: Bouloc
authors: MRC Technology, Centre for Therapeutics Discovery, Mill Hill, London, United Kingdom.
authors: Ela
authors: E
authors: Smiljanic-Hurley
authors: Division of Parasitology, MRC National Institute for Medical Research, Mill Hill, London, United Kingdom.
authors: Barbara
authors: B
authors: Clough
authors: Division of Parasitology, MRC National Institute for Medical Research, Mill Hill, London, United Kingdom.
authors: Robert W
authors: RW
authors: Moon
authors: Division of Parasitology, MRC National Institute for Medical Research, Mill Hill, London, United Kingdom.
authors: Judith L
authors: JL
authors: Green
authors: Division of Parasitology, MRC National Institute for Medical Research, Mill Hill, London, United Kingdom aholder@nimr.mrc.ac.uk.
authors: Anthony A
authors: http://orcid.org/0000-0002-8490-6058
authors: AA
authors: Holder
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D010962:Plasmodium berghei / Q000187:drug effects / Q000472:pathogenicity; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology* / Q000472:pathogenicity; D010966:Plasmodium vivax / Q000187:drug effects / Q000472:pathogenicity; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011494:Protein Kinases / Q000378:metabolism*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases
chemical_list: D000962:Antimalarials; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D015800:Protozoan Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases