STAT3, the signal transducer and activator of transcription 3, is a transcription factor that transmits signals directly from cell surface receptors to the nucleus. Persistent activation of STAT3 signaling has been demonstrated to contribute directly to oncogenesis by stimulating cell proliferation and preventing apoptosis in human cancer cells. Activation of STAT3 not only provides a growth advantage to tumor cells, allowing their accumulation, but also confers resistance to conventional therapies that rely on apoptotic machinery to eliminate tumor cells. STAT3 is thus an attractive cancer therapeutic target. Herein we report the structure-based design, synthesis and evaluation of a new class of conformationally constrained peptidomimetic inhibitors of STAT3. Our efforts have produced a set of compounds that bind to STAT3 with high affinities. Furthermore, by incorporating a long hydrocarbon chain into one STAT3 ligand to improve cell-permeability, we have successfully obtained a potent and cell-permeable STAT3 inhibitor.

Structure-based design of potent, conformationally constrained, cell-permeable STAT3 inhibitors

240th National Meeting (2010)

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