Plasmodial Kinase Inhibitors: License to Cure?

Abstract

Advances in the genetics, function, and stage-specificity of Plasmodium kinases has driven robust efforts to identify targets for the design of antimalarial therapies. Reverse genomics following phenotypic screening against Plasmodia or related parasites has uncovered vulnerable kinase targets including PI4K, PKG, and GSK-3, an approach bolstered by access to human disease-directed kinase libraries. Alternatively, screening compound libraries against Plasmodium kinases has successfully led to inhibitors with antiplasmodial activity. As with other therapeutic areas, optimizing compound ADMET and PK properties in parallel with target inhibitory potency and whole cell activity becomes paramount toward advancing compounds as clinical candidates. These and other considerations will be discussed in the context of progress achieved toward deriving important, novel mode-of-action kinase-inhibiting antimalarial medicines.

Figure 1

(A) Phylogenetic tree for a set of 38 well-characterized protein kinases in P. falciparum. The bootstrap tree was generated from 500 replicates using the neighbor-joining method on the full protein sequence with evolutionary distances computed using the Poisson correction method in the Mega7 software package. Colored labels indicate kinases discussed in this Perspective. Lipid kinases PI3K and PI4K were not included in the analysis. (B) Crystal structure (PDB: 4RZ7) of P. vivax PKG with inhibitor illustrating key interaction in the ATP binding site. (C) Crystal structure (PDB: 4RZ7) of P. vivax PKG inhibitor (cyan) superimposed with dasatinib (purple) from the X-ray structure with activated ABL kinase (PDB: 2GQG). Both inhibitors access the “deep hydrophobic pocket” extending past the threonine gatekeeper residue.

Figure 2

Imidazopyridazine inhibitors of PfCDPK1 and PfPKG.

Figure 3

2,6,9-Trisubstituted purine inhibitor of PfCDPK1, purfalcamine 5.

Figure 4

Indolizine 6 and imidazopyridazine 7 inhibitors of PfCDPK1.

Figure 5

Bumped kinase inhibitors 8 and 9.

Figure 6

Aminopyrazole-carboxamide inhibitors of PfCDPK4 and Trifluoperazine 12.

Figure 7

Inhibitors of cGMP-dependent kinase (PKG).

Figure 8

Quinolinone and oxindole-based inhibitors of PfMRK.

Figure 9

Chalcone and sulfonamide-based and flavonoid inhibitors of PfMRK.

Figure 10

PfGSK-3 inhibitors.

Figure 11

Chemical structures, enzyme, and whole cell activities of PfNEK-1 inhibitors.

Figure 12

Chemical structure of emodin and a CpFIKK inhibitor.

Figure 13

Chemical structures of compounds known to inhibit PfPI3K.

Figure 14

Imidazopyridine/pyrazine compounds as PfPI4K inhibitors.

Figure 15

Homology model of PfPI4K with compound 33 (KAI407), illustrating a key interaction in the ATP binding site (Eyermann, unpublished).

Figure 16

Aminopyridine/pyrazine compounds as PfPI4K inhibitors.