to poor inhibitor protein complementarity substitution of iss610 at the acidic terminus had been shown previously to decrease potency in all cases studied suggesting that the oxazole scaffold is able to project substituents in a substantially different orientation than could be achieved with a peptide based inhibitor fig1 five compounds shown in table 1 displayed ic 50 values below 100 u03bcm with oxazole 10 showing significant dimer disruption potential ic 50 33 u03bcm data suggest limited isoform specificity for stat3 over stat1 protein dramatic effects were observed though replacement of the central core in several cases examples of such effects include compounds 10 and 11 as shown in table 1 where the high potency displayed by the oxazole analog 10 ic 50 33 u03bcm see fig2 a is severely diminished in the analogous thiazole 11 ic 50 775 u03bcm conversely thiazole 16 ic 50 25 u03bcm exhibits improvements in activity compared with the corresponding oxazole 15 ic 50 58 u03bcm molecular modeling studies showed that the thiazole scaffolds afforded a functional group orientation with higher protein surface complementarity docking studies predict a h bond between lys591 and the heterocyclic core oxygen or sulfur which is expected to be more favorable with harder oxazole oxygen atoms than softer thiazole sulfur in almost all examples increased potency is derived from a thiazole core control oxazole compound 12 containing the most potent arrangement of r 1 and r 2 elements but lacking a phosphate group was shown to be essentially devoid of activity further non phosphorylated scaffolds were prepared and found to be impotent stat3 disruptors given the extended planar aryl oxazole construct and the propensity of such scaffolds to intercalate with dna experiments were conducted to discount potential dna interaction it was found using fluorescence spectroscopy that dna bound ethidium bromide.