Dr. Zhong-Yin Zhang

Chemical Biology and Therapeutic Targeting of Protein Tyrosine Phosphatases

Proper level of protein tyrosine phosphorylation, coordinated by the reversible and dynamic action of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), is essential for cell growth and survival. Aberrant protein tyrosine phosphorylation, due to perturbed balance between the activities of PTKs and PTPs, is linked to the etiology of numerous human diseases. Consequently, signaling events driven by protein tyrosine phosphorylation offer a rich source of molecular targets for therapeutic interventions. Research in this laboratory spans the disciplines of chemistry and biology with an emphasis on the structure and function of protein tyrosine phosphatases (PTPs), and development of PTP inhibitors as chemical probes to interrogate PTP function and as novel therapeutics for cancer, diabetes and obesity, autoimmune disorders, neurodegenerative and infectious diseases.

To delineate PTP function, we utilize biochemical, cellular, genetic, and proteomic approaches to probe the roles of PTPs in cellular signaling. Specifically, we carry out detailed mechanistic and kinetic study of PTP-catalyzed reactions. Understanding the molecular basis for protein tyrosine dephosphorylation by PTPs will open doors to new experimental approaches that will elucidate mechanisms by which these enzymes control cell functions. We employ high-affinity PTP substrate-trapping mutants in combination with mass spectrometry for rapid isolation, identification, and characterization of physiological PTP substrates. This will help elucidate the function of individual PTPs as well as assignment of PTPs to specific signaling pathways. We design activity-based probes to globally analyze PTP activity both in normal physiology and in pathological conditions. The ability to profile the entire PTP family on the basis of changes in their activity should greatly accelerate both the assignment of PTP function and the identification of potential therapeutic targets. We also employ state-of-the-art molecular and mouse genetic techniques (e.g. CRISPR gene editing, siRNA silencing, and gene knockout) to define the roles of PTPs in normal physiology and in diseases.

To facilitate therapeutic targeting of the PTPs, we have established a unique academic chemical genomic program encompassing high-throughput screening, structure-based design, and medicinal chemistry to develop small molecule PTP probes for functional interrogation, target identification/validation, and therapeutic development. To this end, we have pioneered a novel paradigm for the acquisition of potent and selective PTP inhibitors by targeting both the PTP active site and unique pockets in the vicinity of the active site. We have developed a number of nonhydrolyzable pTyr pharmacophores that are sufficiently polar to bind the PTP active site, yet remain capable of efficiently crossing cell membranes, offering PTP inhibitors with both high potency and excellent in vivo efficacy in animal models of oncology, diabetes/obesity, autoimmunity, and tuberculosis. Current efforts aim to advance our lead generation and optimization paradigms and to create a 'PTP-based drug discovery platform' that will ultimately impact broadly the portfolio of tomorrow.

Students and postdoctoral fellows will have the opportunity to interact with a highly interactive, collaborative and multi-disciplinary group of individuals with expertise ranging from biochemistry and cell biology, mouse genetics, structural biology, chemical biology and medicinal chemistry.

Education

• B.S., Nankai University, Chemistry, 1984
• Ph.D., Purdue University, Chemistry, 1990
• Postdoctoral Fellow, The Upjohn Company, 1991
• Postdoctoral Fellow, University of Michigan, 1994

Publications

List of publications