Genetic lesions in SHP-2, a protein tyrosine phosphatase that has been previously shown by us to play an overall positive role in hematopoietic cell development and function, have recently been identified in the inherited developmental disorder Noonan syndrome and childhood leukemias, such as juvenile myelomonocytic leukemia (JMML). These mutations cause hyperactivation of SHP-2 catalytic activity. Additionally, recent studies, including ours, have shown that the leukemia associated mutations also enhance interactions of SHP-2 with its signaling partners. The SHP-2 gain-of-function (GOF) mutations and Ras or Neurofibromatosis 1 (Nf1) mutations are mutually exclusive in the patients. Furthermore, single SHP-2 GOF mutations (D61G or E76K) induce Noonan syndrome and JMML-like myeloid proliferative disease in mice, suggesting that the SHP-2 GOF mutations play a causal role in the pathogenesis of these diseases. The direct connection between activating mutations of SHP-2 and JMML and Noonan syndrome suggests that SHP-2 may be a useful target for mechanism-based therapeutics for these diseases. Therefore, it is very important to develop selective SHP-2 inhibitors. The availability of SHP-2 specific inhibitors could lead to the development of new drugs that would ultimately serve as treatments for JMML and Noonan syndrome. In the proposed study we will use our combined expertise in computer-aided drug design (CADD) and SHP-2 biology to identify promising low molecular weight (lead) compounds that specifically inhibit SHP-2 enzymatic activity or that block its phosphotyrosine (pY)-dependent, protein interaction capability. In preliminary studies the proposed approaches have been applied to successfully identify compounds designed to bind to a region of the catalytic domain that has structural features unique to SHP-2 thereby maximizing the potential that the compounds will be specific for SHP-2 versus other phosphatases. In the proposed study this success will be extended to accomplish our goal of developing potent and selective SHP-2 inhibitors. A virtual database of >3 million commercially-available low-molecular weight compounds will be screened against the 3D structure of SHP-2. Compounds selected by the CADD screening will then be assessed by in vitro experimental assays in order to identify those with the desired biological activity. Direct binding interactions between biologically-active compounds and SHP-2 protein will also be determined. Successful compounds will be further validated for their effectiveness and specificity through the use of hematopoietic cell models. It is anticipated that this study will identify selective and effective SHP-2 inhibitors that can be used as lead compounds for the development of novel therapeutic agents for SHP-2-associated diseases, such as JMML and Noonan syndrome. ? ? ?
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