Over 100 human proteins use Src Homology 2 (SH2) domains to modulate signaling by recognizing phosphotyrosine-containing sequences. In disease, these signaling pathways often become dysregulated. For example, the transcription factor Signal Transducer and Activator of Transcription 3 (STAT3) is constitutively activated in most hematological malignancies and many solid tumors. While STAT3 and many other SH2-domain-containing proteins are still without molecular therapeutics, targeting their SH2 domains could provide a successful strategy for inhibiting their activity.<br/><br/>The major challenge to targeting SH2 domains is the poor pharmacological profile of phosphotyrosine and its isosteres.  Extensive medicinal chemistry has suggested that mimicking phosphotyrosine requires multiple negative charges, but such functional groups generally have poor pharmacokinetic profiles, including low cell penetration.  Previous work in our lab indicated that, with the right conformational constraint, phosphotyrosine mimicry can be achieved with a monocarboxylate in the context of a highly constrained peptide.  These and other findings have led us to hypothesize that constrained peptides may be a general means of mimicking phosphotyrosine using a single carboxylate.<br/><br/>To test this hypothesis, we have devised and screened high combinatorial peptide libraries to identify phosphotyrosine-mimicking peptides that selectively inhibit the STAT3-SH2 domain. We optimized suitable one-bead-one-compound synthesis, screening, and sequencing strategies, and with the use of conformationally constraining artificial amino acids, are identifying peptides that bind STAT3. Library hits undergo secondary validation and cell-based assays to demonstrate STAT3-SH2 binding, cell penetration, and inhibition of transcriptional activity. This approach is designed to identify new peptides that not only inhibit the STAT3-SH2 domain, but provide a model for targeting additional disease-relevant, phosphotyrosine-binding proteins.

Developing phosphotyrosine-mimicking peptides for the inhibition of the STAT3 SH2 domain

256th National Meeting (2018)

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