Efforts are focused on the design, synthesis and evaluation of polypeptides that are targeted to inhibit, or otherwise modulate key cellular signal transduction processes. The long term goal is to develop effective agents that are selective in inhibiting the oncogenic cell proliferative signal, or to boost the effectiveness of tumor suppressor proteins, and thus could become useful cancer therapeutic agents. Two major projects were undertaken. In one of these the mode of action of the cell cycle inhibitory protein, p21(Waf1/Cip1) was studied. For this purpose the protein was synthesized with overlapping peptide segments. The very C-terminal segment was found to efficiently inhibit the kinase activity of several cyclin/Cdk complexes, with retinoblastoma protein as substrate. A chimeric molecule was devised, consisting of the cdk inhibitor and a generic 'cell permeable peptide'. This chimeric agent showed a strong necrotic or apoptotic effect on CA46 cells in culture, and our collaborators (P.O'Connor,et al) are evaluating the nature of this cellular response. In a second project area, we have developed redox stable cyclic non-phosphotyrosine containing peptides that bind with selectivity to the SH2 domain of the docking protein Grb2. Grb2 functions in cellular signalling through the oncogenic ras activation pathway. The mechanism of binding of cyclic peptides to Grb2 is being studied by evaluation of alanine mutant analogs, by NMR based 3 dimensional structure studies, and by X-ray studies of the cyclic peptide/Grb2 complexes.
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