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Signal transducer and activator of transcription 3 (Stat3) transmits signals from growth factors and interleukin-6 family cytokines by binding to their receptors via its Src homology 2 (SH2) domain. This results in phosphorylation of Tyr705, dimerization, translocation to the nucleus, and regulation of transcription of downstream genes. Stat3 is constitutively activated in several human cancers and is a target for anti-cancer drug design. We have shown previously phosphorylation of Tyr705 in intact cancer cells can be inhibited with prodrugs of phosphopeptide mimics targeting the SH2 domain. In a series of prodrugs consisting of bis-pivaloyloxymethyl esters of 4'-phosphonodifluoromethyl cinnamoyl-Haic-Gln-NHBn, appending methyl group to the β -position of the cinnamate increased potency ca. twofold, which paralleled the increase in affinity of the corresponding phosphopeptide models. However, dramatic increases in potency were observed when the C-terminal C(O)NHBn of Gln-NHBn was replaced with a simple methyl group. In this communication we continue to explore the effects of structural modifications of prodrugs on their ability to inhibit Tyr705 phosphorylation. A set of 4-substituted prolines incorporated into β -methyl-4-phosphocinnamoyl-leucinyl-Xaa-4-aminopentamide model peptides exhibited affinities of 88-317 nM by fluorescence polarization (Pro IC 50 = 156 nM). In corresponding prodrugs, Pro inhibited constitutive Stat3 phosphorylation at 10 μM in MDA-MB-468 breast tumor cells. However, 4,4-difluoroproline and 4,4-dimethylproline resulted in complete inhibition at 0.5 μM. These results suggest that the prodrug with native proline undergoes metabolism that those with substituted prolines do not. In conclusion, changes in structure with minimal impact on intrinsic affinity can nevertheless have profound effects on the cellular potency of prodrug inhibitors of Stat3.

international journal of peptide research and therapeutics

Structure–Activity Studies of Phosphopeptidomimetic Prodrugs Targeting the Src Homology 2 (SH2) Domain of Signal Transducer and Activator of Transcription 3 (Stat3)