A phosphopeptide mimetic prodrug targeting the SH2 domain of Stat3 inhibits tumor growth and angiogenesis
Edmond J. Auzenne, Jim Klostergaard, Pijus K. Mandal, Warren S. Liao, Zhen Lu, Fengqin Gao, Robert C. Bast Jr., Fredika M. Robertson and John S. McMurray
Signal transducer and activator of transcription 3 (Stat3) is constitutively activated in a number of human cancers and cancer cell lines. Via its Src homology 2 (SH2) domain, Stat3 is recruited to phosphotyrosine residues on intracellular domains of cytokine and growth factor receptors, whereupon it is phosphorylated on Tyr705, dimerizes, translocates to the nucleus and is reported to participate in the expression of genes related to angiogenesis, metastasis, growth and survival. To block this process, we are developing cell-permeable, phosphatase-stable phosphopeptide mimics, targeted to the SH2 domain of Stat3, that inhibit the phosphorylation of Tyr705 of Stat3 in cultured tumor cells (Mandal et al., J. Med. Chem. 54, 3549-5463, 2011). At concentrations that inhibit tyrosine phosphorylation, these materials were not cytotoxic, similar to recent reports on JAK inhibitors. At higher concentrations, cytotoxicity was accompanied by off-target effects. We report that treatment of MDAMB- 468 human breast cancer xenografts in mice with peptidomimetic PM-73G significantly inhibited tumor growth, which was accompanied by reduction in VEGF production and microvessel density. No evidence of apoptosis or changes in the expression of the canonical genes cyclin D1 or survivin were observed. Thus selective inhibition of Stat3 Tyr705 phosphorylation may be a novel anti-angiogenesis strategy for the treatment of cancer.
Keywords: Signal transducer and activator of transcription 3, Stat3, SH2 domain, phosphopeptide prodrug, angiogenesis