The non-receptor protein tyrosine phosphatase SHP-2 is a key cell-signaling molecule in vertebrates that plays roles in normal development and hematopoiesis. Composed of two successive Src homology 2 (SH2) domains followed by a phosphatase domain, SHP-2 is self-inhibited by binding of the N-terminal SH2 domain to the phosphatase domain. Mutations at the binding interface of these two domains that cause loss of self- inhibition are associated with acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, and acute monocytic leukemia as well as the developmental disease Noonan syndrome.
The specific aims of the proposed work are: 1) identify small molecules with the potential to act as inhibitors of SHP-2 phosphatase activity using in silico database screening, including development of a novel approach to include bridging waters in the docking process; 2) select those compounds identified in aim 1 with the desirable biological activity through in vitro phosphatase assays; and 3) systematically modify the identified lead compounds from aim 2 to further increase the efficacy of their SHP-2 phosphatase inhibition. The developed inhibitors will serve as research tools and potential precursors to therapeutics for leukemia and Noonan syndrome. ? ?
