Research Abstracts Online
January - December 2011
Mayo Clinic College of Medicine
PI: Ian Parney
The Rational Design, Synthesis, and Evaluation of Novel STAT3 Inhibitors for Treatment of Malignant Gliomas
The signal transducer and activator of transcription-3 (STAT3) oncogene is a promising molecular target for the development of novel drugs in the treatment of malignant gliomas. STAT3 activation drives both cell proliferation and tumor-mediated immunosuppression. It is constitutively activated in specimens from cancer patients and human cancer cell lines (including malignant gliomas), but not in normal cells. STAT3 activation occurs through phosphorylation of tyrosine 705, which results in formation of a STAT3 homodimer that translocates to the nucleus and regulates the expression of various oncogenes. The critical step in STAT activation is the dimerization between two STAT monomers. These researchers hypothesize that a direct small molecule STAT3 inhibitor can be designed through a rational drug discovery process that would be a novel therapeutic agent for malignant gliomas with constitutive STAT3 activation. Using the key structural information from the x-ray crystal structure of the STAT3 homodimer, they use modeling and docking studies to design small molecules that mimic the native phosphotyrosine peptide. This will potentially disrupt the STAT3-STAT3 protein-protein interactions and inhibit its activity. The researchers will determine the ability to inhibit the STAT3-STAT3 complex through a previously published in vitro DNA-binding assay.
David Daniels, Research Associate