The protein kinase promiscuities in the cancer-preventive mechanisms of NSAIDs

Abstract

NSAIDs have been observed to have cancer-preventive properties, but the actual mechanism is elusive. We hypothesize that NSAIDs might have an effect through common pathways and targets of anticancer drugs by exploiting promiscuities of anticancer drug targets. Here, we have explored NSAIDs by their structural and pharmacophoric similarities with small anticancer molecules. In-silico analyses have shown a strong similarity between NSAIDs and protein kinase (PK) inhibitors. The calculated affinities of NSAIDs were found to be lower than the affinities of anticancer drugs, but higher than the affinities of compounds that are not specific to PKs. The competitive inhibition model suggests that PK might be inhibited by around 10%, which was confirmed by biochemical screening of some NSAIDs against PKs. NSAIDs did not affect all PKs universally, but had specificities for certain sets of PKs, which differed according to the NSAID. The study revealed potentially new features and mechanisms of NSAIDs that are useful in explaining their role in cancer prevention, which might lead to clinically significant breakthroughs in the future.

Fig. 1

Heatmap of a similarity matrix with a corresponding dendrogram based on pharmacophoric alignments and physicochemical pairwise comparisons of different classes of anticancer drugs and NSAIDs. Brighter shades show greater similarities. COX, cyclooxygenase.

Fig. 2

Heatmap of a similarity matrix based on pharmacophoric and physicochemical ligand–ligand comparisons between anticancer drugs and NSAIDs. COX, cyclooxygenase; PK, protein kinase.

Fig. 3

The virtual screening results of NSAIDs against PKs. (a) Docked nilotinib (gray structure) perfectly overlaps with the crystal structure of nilotinib (black structure), with a root mean square deviation (RMSD) of 0.37 Å. Docked meclofenamic acid (white structure) overlaps with nilotinib fragments in the ABL1 pocket. (b) Comparison of average calculated affinities of chemotherapeutic compounds, ATP, NSAIDs, and metabolites. Dockings were performed in the selected targets of anticancer drugs. Chemo, chemotherapeutic; PK, protein kinase.

Fig. 4

The catalytic kinetics of PK targets interpreted by competitive inhibition. (a) The reduced reaction rate without inhibition (V₀) and with inhibitors (V_chem, anticancer drugs; V_NSAID, NSAIDs) as a function of the physiological ATP concentrations. The numbers denote the NSAID C_max concentration used to calculate V/V_max. (b) The target fraction inactivated by chemotherapeutics and NSAIDs on the basis of their average calculated affinities as a function of their concentrations. Chemo, chemotherapeutic; PK, protein kinase.

Fig. 5

Activity of PKs with some NSAIDs at a 100 μmol/l concentration in the biochemical screening. Top: averages (the horizontal line inside boxes) with SD (box vertical size) and min/max values (whiskers). Bottom: activity heatmap (brighter shades indicate higher inhibition). PK, protein kinase.

Fig. 6

Network with common targets for anticancer drugs, color-coded according to the cumulative affinity (grayscale background: darker shades, higher affinity) for NSAIDs.