Design, synthesis and in vitro characterization of novel hybrid peptidomimetic inhibitors of STAT3 protein
Abbreviated Journal Title
Bioorg. Med. Chem.
STAT3; Peptidomimetics; SH2 domain; Molecular recognition; Anti-cancer; drugs; Protein-protein interactions; EPIDERMAL-GROWTH-FACTOR; BREAST-CARCINOMA CELLS; SIGNAL TRANSDUCER; CONSTITUTIVE ACTIVATION; SMALL-MOLECULE; FLUORESCENCE POLARIZATION; BIOLOGICAL-ACTIVITY; GENE-REGULATION; SH2 DOMAIN; CANCER; Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, ; Organic
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 mu M) 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. (C) 2010 Elsevier Ltd. All rights reserved.
Bioorganic & Medicinal Chemistry
"Design, synthesis and in vitro characterization of novel hybrid peptidomimetic inhibitors of STAT3 protein" (2011). Faculty Bibliography 2010s. 1888.