Research Project
9169187
Project Summary The protein tyrosine phosphatases (PTPs), which dephosphorylate specific phosphotyrosine residues in protein substrates, constitute a large family of signaling enzymes, whose activity is ubiquitously misregulated in human diseases such as leukemias, solid-tumor cancers, type I and type II diabetes, and autoimmune disorders. Tools that are capable of inducing target-specific PTP inhibition or activation would be invaluable for delineation of the precise functions of PTPs in cell signaling and for the validation of PTPs as therapeutic targets. However, the common architecture of the conserved PTP-domain fold impedes the discovery of selective PTP inhibitors, and cell-permeable PTP activators have not been identified to date. The broad objective of the proposed research is to develop tools to specifically inhibit or activate PTP enzymes by targeting either engineered cysteine residues (Specific Aim 1) or naturally occurring cysteine residues (Specific Aim 2). Specific Aim 1 (Target-specific inhibition and activation of engineered PTPs with biarsenical small molecules) proposes several complementary means for engineering inhibitor- sensitive and activator-sensitive (collectively, ligand-sensitive) PTPs: engineered phosphatases whose activities are uniquely responsive to small molecules. The proposed inhibitor- and activator-sensitization strategies, which can potentially be applied widely across the PTP superfamily, will afford PTP-signaling researchers an unprecedented level of chemical control with which to study a key family of signaling enzymes. Specific Aim 2 (Targeting naturally occurring cysteine residues for the discovery of Shp2- specific inhibitors and activators) is focused on selectively targeting naturally occurring cysteine residues in a medicinally important PTP, Shp2, with the goal of discovering compounds that have direct implications for drug development. The proposed experiments are aimed at the discovery of drug-like compounds that can target Shp2?s unique allosteric site, potentially providing highly selective Shp2 inhibitors that have not been realized through active-site- directed efforts. Also proposed are small-molecule-discovery efforts targeting two disease- causing Shp2 mutants that contain missense cysteine residues (Y63C and Y279C Shp2, which cause Noonan and LEOPARD syndromes, respectively). Both mutations affect the enzymatic activity of Shp2; efforts to identify compounds that restore wild-type-like Shp2 function by targeting the disease-causing cysteine residues are proposed.
