Abstract
Inhibition of protein-protein interactions by small molecules offers tremendous opportunities for basic research and drug development. One of the fundamental challenges of this research field is the broad lack of available lead structures from nature. Here, we demonstrate that modifications of a chromone-based inhibitor of the Src homology 2 (SH2) domain of the transcription factor STAT5 confer inhibitory activity against STAT3. The binding mode of the most potent STAT3 inhibitor Erasin was analyzed by the investigation of structure-activity relationships, which was facilitated by chemical synthesis and biochemical activity analysis, in combination with molecular docking studies. Erasin inhibits tyrosine phosphorylation of STAT3 with selectivity over STAT5 and STAT1 in cell-based assays, and increases the apoptotic rate of cultured NSCLC cells in a STAT3-dependent manner. This ability of Erasin also extends to HCC-827 cells with acquired resistance against Erlotinib, a clinically used inhibitor of the EGF receptor. Our work validates chromone-based acylhydrazones as privileged structures for antagonizing STAT SH2 domains, and demonstrates that apoptosis can be induced in NSCLC cells with acquired Erlotinib resistance by direct inhibition of STAT3.
Highlights
Since protein-protein interactions mediate most biological processes, their inhibition by small molecules has tremendous potential for use in the study of cellular pathways, and for therapeutic interventions[1,2,3,4,5]
The STAT family display a high degree of homology
In order to assess whether the scaffold of the most potent STAT5 inhibitor 1 (Table 1, entry 1)[22,23] could be utilized for inhibition of other STAT family members, we explored the effect of substitutions at the 6-position of the chromone ring
Summary
The STAT family display a high degree of homology. In order to assess whether the scaffold of the most potent STAT5 inhibitor 1 (Table 1, entry 1)[22,23] could be utilized for inhibition of other STAT family members, we explored the effect of substitutions at the 6-position of the chromone ring. The control compound 9 did not increase the apoptotic rate of either HCC-827 cell line (Fig. 4d,f), and did not reduce STAT3 Tyr[705] phosphorylation (Fig. 4g,h), indicating that the induction of apoptosis by 8 in both parental HCC-827 and Erlotinib-resistant HCC-827 cells is caused by inhibition of STAT3. 8 represents the first chromone-based acylhydrazone shown to target STAT3 with selectivity over STAT5 and STAT1 in cell-based assays, and increases the apoptotic rate of cultured NSCLC cells in a STAT3-dependent manner This ability of 8 extends to HCC-827 cells which have acquired resistance against Erlotinib, a clinically used inhibitor of the EGF receptor. Chromone-based acyl hydrazones represent a rare case of natural product-based structures that can be fine-tuned to inhibit members of protein-protein interaction domains by simple variation of the substitution pattern[18,48]
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