The research interests of the Bishop laboratory are predominantly focused at the interface between organic chemistry and molecular biology. We use a combination of chemical and biochemical approaches to study complex biological processes such as cellular signal transduction. Some ongoing projects of the lab are described in greater detail below.
Target-specific control of protein tyrosine phosphatase activity
Protein tyrosine phosphatases (PTPs) are enzymes that help to send cellular messages by enzymatically removing phosphate groups from other proteins. When cellular phosphate removal goes awry, so do the basic regulatory mechanisms of the cell, and improperly regulated PTP activity has been implicated as a causative agent in a range of human diseases, including cancer, diabetes, and neurodegenerative disorders. Research in the Bishop lab focuses on the design of small-molecule PTP inhibitors and activators that achieve selectivity by covalently engaging non-conserved cysteine residues within the target PTPs of interest.
One particular PTP, 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. Many of our efforts center on the discovery of selective inhibitors and activators of SHP2 and its disease-associated cysteine mutants, providing direct leads for SHP2-directed pharmaceutical development.
In a project that focuses on a different PTP, we seek to discover 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. We are working to develop selective covalent TCPTP inhibitors that engage a cysteine residue within TCPTP’s catalytic domain. These studies 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.