Optimization of potent DFG-in inhibitors of platelet derived growth factor receptorβ (PDGF-Rβ) guided by water thermodynamics.

In this study we report on the hit optimization of substituted 3,5-diaryl-pyrazin-2(1H)-ones toward potent and effective platelet-derived growth factor receptor (PDGF-R) beta-inhibitors. Originally, the 3,5-diaryl-pyrazin-2-one core was derived from the marine sponge alkaloid family of hamacanthins. In our first series compound 2 was discovered as a promising hit showing strong activity against PDGF-R beta in the kinase assay (IC50 = 0.5 mu M). Furthermore, 2 was shown to be selective for PDGF-R beta in a panel of 24 therapeutically relevant protein kinases. Molecular modeling studies on a PDGF-R beta homology model using prediction of water thermodynamics suggested an optimization strategy for the 3,5-diaryl-pyrazin-2-ones as DFG-in binders by using a phenolic OH function to replace a structural water molecule in the ATP binding site. Indeed, we identified compound 38 as a highly potent inhibitor with an IC50 value of 0.02 mu M in a PDGF-R beta enzymatic assay also showing activity against PDGF-R dependent cancer cells.