Title

Design, Synthesis And In Vitro Characterization Of Novel Hybrid Peptidomimetic Inhibitors Of Stat3 Protein

Keywords

Anti-cancer drugs; Molecular recognition; Peptidomimetics; Protein-protein interactions; SH2 domain; STAT3

Abstract

Aberrant activation of oncogenic signal transducer and activator of transcription 3 (STAT3) protein signaling pathways has been extensively implicated in human cancers. Given STAT3's prominent dysregulatory role in malignant transformation and tumorigenesis, there has been a significant effort to discover STAT3-specific inhibitors as chemical probes for defining the aberrant STAT3-mediated molecular events that support the malignant phenotype. To identify novel, STAT3-selective inhibitors suitable for interrogating STAT3 signaling in tumor cells, we explored the design of hybrid molecules by conjugating a known STAT3 inhibitory peptidomimetic, ISS610 to the high-affinity STAT3-binding peptide motif derived from the ILR/gp-130. Several hybrid molecules were examined in in vitro biophysical and biochemical studies for inhibitory potency against STAT3. Lead inhibitor 14aa was shown to strongly bind to STAT3 (K D = 900 nM), disrupt STAT3:phosphopeptide complexes (K i = 5 μM) and suppress STAT3 activity in in vitro DNA binding activity/electrophoretic mobility shift assay (EMSA). Moreover, lead STAT3 inhibitor 14aa induced a time-dependent inhibition of constitutive STAT3 activation in v-Src transformed mouse fibroblasts (NIH3T3/v-Src), with 80% suppression of constitutively-active STAT3 at 6 h following treatment of NIH3T3/v-Src. However, STAT3 activity recovered at 24 h after treatment of cells, suggesting potential degradation of the compound. Results further showed a suppression of aberrant STAT3 activity in NIH3T3/v-Src by the treatment with compound 14aa-OH, which is the non-pTyr version of compound 14aa. The effect of compounds 14aa and 14aa-OH are accompanied by a moderate loss of cell viability. © 2011 Elsevier Ltd. All rights reserved.

Publication Date

3-1-2011

Publication Title

Bioorganic and Medicinal Chemistry

Volume

19

Issue

5

Number of Pages

1823-1838

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1016/j.bmc.2010.12.010

Socpus ID

79952189441 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/79952189441

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