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[摘要]：Virtual screening methods combined with exptl. assays were used to identify low mol. wt. inhibitors for Src homol. 2 domain-contg. phosphatase 2 (SHP-2) that is mutated and hyperactivated in Noonan syndrome and a significant portion of childhood leukemias. Virtual screening included multiple conformations of the protein, score normalization procedures, and chem. similarity considerations. As the catalytic core of SHP-2 shares extremely high homol. to those of the related SHP-1 phosphatase and other tyrosine phosphatases, in order to identify selective inhibitors, we chose to target an adjacent protein surface pocket that is predicted to be important for binding to phosphopeptides and that has structural features unique to SHP-2. From a database of 1.3 million compds., 9 out of 165 computationally selected compds. were shown to inhibit SHP-2 activity with IC50 values of u 100 mM. Two of the active compds. were further verified for their ability to inhibit SHP-2-mediated cellular functions. Fluorescence titrn. expts. confirmed their direct binding to SHP-2. Because of their simple chem. structures, these small org. compds. have the potential to act as lead compds. for the development of novel anti-SHP-2 drugs. |
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