STAT3 hyperphosphorylation, dimerization and DNA binding are required for its ability to contribute to malignant transformation. As such, STAT3 has been recognized as a promising target for cancer therapy. Although a number of inhibitors of STAT3-STAT3 dimerization have been reported, molecular ligands that prevent interactions between STAT3 and DNA are very rare. The Î³-AApeptide-based one-bead-one-compound (OBOC) combinatorial library was used, and identified Î³-AApeptides that can selectively inhibit STAT3/DNA interaction and suppress the expression levels of STAT3 target genes in intact cells. The results not only validate Î³-AApeptides as novel inhibitors of STAT3 signaling pathway, but also demonstrate that in addition to the SH2 domain, the DNA binding domain of STAT3 is targetable for the development of new generation of anti-cancer therapeutics. This also validates the approach of OBOC combinatorial library for the identification of ligands targeting traditionally recognized âundruggable targetsâ.
Sebti, Said M. and Cai, Jianfeng, "Gamma-AA-peptide STAT3/DNA inhibitors and methods of use" (2018). USF Patents. 1045.
H. Lee Moffitt Cancer Center and Research Institute, Inc.