Optimization of Potent <i>DFG-in</i> 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(1<i>H</i>)-ones toward potent and effective platelet-derived growth factor receptor (PDGF-R) β-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 <b>2</b> was discovered as a promising hit showing strong activity against PDGF-Rβ in the kinase assay (IC₅₀ = 0.5 μM). Furthermore, <b>2</b> was shown to be selective for PDGF-Rβ in a panel of 24 therapeutically relevant protein kinases. Molecular modeling studies on a PDGF-Rβ homology model using prediction of water thermodynamics suggested an optimization strategy for the 3,5-diaryl-pyrazin-2-ones as <i>DFG-in</i> binders by using a phenolic OH function to replace a structural water molecule in the ATP binding site. Indeed, we identified compound <b>38</b> as a highly potent inhibitor with an IC₅₀ value of 0.02 μM in a PDGF-Rβ enzymatic assay also showing activity against PDGF-R dependent cancer cells

IMINORIBITOL-MODIFIED 3,4-DIARYL-ISOXAZOLES AS POTENT INHIBITORS OF CK1δ/ε

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