Design, synthesis and in vitro characterization of novel hybrid peptidomimetic inhibitors of STAT3 protein

作者：Shahani Vijay M; Yue Peibin; Fletcher Steven; Sharmeen Sumaiya; Sukhai Mahadeo A; Luu Diana P; Zhang Xiaolei; Sun Hong; Zhao Wei; Schimmer Aaron D; Turkson James^*; Gunning Patrick T

来源：Bioorganic & Medicinal Chemistry, 2011, 19(5): 1823-1838.

DOI：10.1016/j.bmc.2010.12.010

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

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.

• 出版日期2011-3-1