title: Design, synthesis, and in vitro characterization of novel hybrid peptidomimetic inhibitors of STAT3 protein.
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 6h following treatment of NIH3T3/v-Src. However, STAT3 activity recovered at 24h 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.
authors.affiliation: Department of Chemistry, University of Toronto, Mississauga, ON, Canada.
authors.forename: Vijay M
authors.initials: VM
authors.lastname: Shahani
authors.forename: Peibin
authors.initials: P
authors.lastname: Yue
authors.forename: Steven
authors.initials: S
authors.lastname: Fletcher
authors.forename: Sumaiya
authors.initials: S
authors.lastname: Sharmeen
authors.forename: Mahadeo A
authors.initials: MA
authors.lastname: Sukhai
authors.forename: Diana P
authors.initials: DP
authors.lastname: Luu
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Zhang
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
authors.forename: James
authors.initials: J
authors.lastname: Turkson
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Gunning
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D057786:Peptidomimetics; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D057786:Peptidomimetics; D050796:STAT3 Transcription Factor