Biochemical and anti-parasitic properties of inhibitors of the Plasmodium falciparum calcium-dependent protein kinase PfCDPK1.

Antimicrobial agents and chemotherapy

PubMedID: 25070106

Ansell KH, Jones HM, Whalley D, Hearn A, Taylor DL, Patin EC, Chapman TM, Osborne SA, Wallace C, Birchall K, Large J, Bouloc N, Smiljanic-Hurley E, Clough B, Moon RW, Green JL, Holder AA. Biochemical and anti-parasitic properties of inhibitors of the Plasmodium falciparum calcium-dependent protein kinase PfCDPK1. Antimicrob Agents Chemother. 2014;.
PfCDPK1 is a Plasmodium falciparum-encoded calcium-dependent protein kinase, which has been identified as a potential target for novel anti-malarial 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 optimisation. 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 IC50 values below 10 nM against PfCDPK1 in a biochemical assay and EC50 values less than 100 nM for inhibition of parasite growth in vitro. Potent inhibition was combined with acceptable ADMET properties and equipotent inhibition of P. vivax CDPK1. However, we were unable to correlate biochemical inhibition with parasite growth inhibition for this series overall. Inhibition of P. berghei CDPK1 was well-correlated 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.