Research Project
10356614
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. Src-Homology-2-domain- containing PTP 2 (SHP2) represents a striking example of the connection between aberrant PTP activity and pathogenesis, as SHP2 mutations cause the developmental disorders Noonan syndrome and LEOPARD syndrome, and elevated SHP2 activity has been strongly associated with the development of human cancers. Specific Aims 1 and 2 of this proposal describe efforts toward the discovery of selective inhibitors and activators of SHP2 and its disease-associated cysteine mutants, providing direct leads for PTP-directed pharmaceutical development. The proposed experiments of Aim 1 will enable the identification of drug-like compounds that can target SHP2?s unique allosteric site, potentially providing highly selective SHP2 inhibitors. Aim 2 describes 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. Specific Aim 3 presents a strategy for the development of selective, allosteric inhibitors of T-cell protein phosphatase (TCPTP). TCPTP has recently emerged as an intriguing drug target, as disruption of TCPTP activity substantially increases the effectiveness of cancer- fighting immunotherapeutic strategies. However, few TCPTP-directed inhibitor studies have been carried out and no TCPTP-selective allosteric or covalent inhibitors have been previously identified. Although an allosteric-inhibition site on TCPTP is known, the site has only been targeted with low potency, reversible ligands that also inhibit TCPTP?s closest homolog, PTP1B. The proposed work will develop selective covalent TCPTP inhibitors that engage C278?a cysteine residue within TCPTP?s allosteric site that is unique to TCPTP among intracellular PTPs?through rational modification of a known allosteric-site ligand with cysteine- reactive electrophiles. This study will expand the range of PTP-domain cysteines that can be targeted for potent and selective allosteric control of PTP activity and will provide a novel strategy for increasing the efficacy of anti-cancer immunotherapy.
