Ph.D. - 1990, Purdue University
Postdoc - 1990-1991, The Upjohn Company
Postdoc - 1991-1994, The University of Michigan
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. The ability to selectively modulate signaling pathways, through inhibition of PTPs, holds enormous therapeutic potential. However, despite the fact that PTPs have been garnering attention as attractive drug targets, they remain largely an untapped resource. Among the contributing factors to the challenge of targeting PTPs for drug discovery is the lack of detailed understanding of how dysregulation of PTP activity cause human diseases. In addition, the PTPs are exceptionally difficult targets for drug discovery due to the highly conserved and positively charged active sites.
Research in this laboratory spans the disciplines of chemistry and biology with an emphasis on the structure and function of protein tyrosine phosphatases (PTPs), roles of PTP in normal physiology and pathological conditions, and the design and synthesis of PTP inhibitors as chemical probes to interrogate PTP function and as novel therapeutics for the treatment of cancer, diabetes and obesity, autoimmune disorders, neurodegenerative and infectious diseases.
To understand the function of PTPs, 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 catalysis and substrate recognition using physiological substrates. Understanding the molecular basis for 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. Identification and characterization of cellular PTP substrates will help elucidate the function of individual PTPs as well as assignment of PTPs to specific signaling pathways. We design activity-based probes to analyze globally 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 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.
Dong, Y., Zhang, L., Zhang, S., Bai, Y., Chen, H., Sun, X., Yong, W., Li, W., Colvin, S. C., Rhodes, S. J., Shou, W., and Zhang, Z.-Y. “Phosphatase of regenerating liver 2 (PRL2) is essential for placenta development by downregulating PTEN (phosphatase and tensin homologue deleted on chromosome 10) and activating Akt protein”, J. Biol. Chem. 287, 32172-32179 (2012).
Zhang, S., Liu, S., Tao, R., Wei, D., Chen, L., Shen, W., Yu, Z.-H., Wang, L., Jones, D. R., Dong, X. C. and Zhang, Z.-Y. “A highly selective and potent PTP-MEG2 inhibitor with therapeutic potential for type 2 diabetes” J. Am. Chem. Soc. 134, 18116-18124 (2012).
He, Y., Xu, J., Yu, Z.-H., Gunawan A. M., Wu, L., Wang, L., and Zhang, Z.-Y. “Discovery and Evaluation of Novel Inhibitors of Mycobacterium Protein Tyrosine Phosphatase B from the 6-Hydroxy-Benzofuran-5-Carboxylic Acid Scaffold”, J. Med. Chem. 56, 832-842 (2013).
He, Y., Liu, S., Menon, A., Stanford, S., Oppong, E., Gunawan, A. M., Wu, L., Wu, D. J., Barrios, A. M., Bottini, N., Cato, A. C., and Zhang, Z.-Y. “A potent and selective small molecular inhibitor for the lymphoid-specific tyrosine phosphatase (LYP), a target associated with autoimmune diseases”, J. Med. Chem. 56, 4990-5008 (2013).
Yu, Z.-H., Xu, J., Walls, C., Chen, L., Zhang, S., Zhang, R., Wu, L., Wang, L., Liu, S., and Zhang, Z.-Y. “Structural and mechanistic insights into LEOPARD syndrome associated SHP2 mutations” J. Biol. Chem. 288, 10472-10482 (2013).
Walls, C., Iliuk, A., Bai, Y., Wang, M., Tao, A. and Zhang, Z.-Y. “Phosphatase of Regenerating Liver 3 (PRL3) Provokes a Tyrosine Phosphoproteome to Drive Pro-Metastatic Signal Transduction”, Molecular and Cellular Proteomics 12, 3759-3777 (2013).
Dong, Y., Zhang, L., Bai, Y., Zhou, H.-M., Campbell, A. M., Chen, H., Yong, W., Zhang, W., Zeng, Q., Shou, W., and Zhang Z.-Y. “Phosphatase of regenerating liver 2 (PRL2) deficiency impairs Kit signaling and spermatogenesis”, J. Biol. Chem. 289, 3799-3810 (2014).
Zeng, L.-F., Zhang, R.-Y., Bai, Y., Wu, L., Gunawan, A. M., and Zhang, Z.-Y. “Hydroxyindole Carboxylic Acid Based Inhibitors for Receptor-Type Protein Tyrosine Protein Phosphatase Beta”, Antioxidants & Redox Signaling 20, 2130-2140 (2014).
Kobayashi, M., Bai, Y., Dong, Y., Yu, H., Chen, S., Gao, R., Zhang, L. Yoder, M. C., Kapur, R., Zhang Z.-Y. and Liu, Y. “PRL2/PTP4A2 phosphatase is important for hematopoietic stem cell self-renewal”, Stem Cells 32, 1956-1967 (2014).
Zeng, L.-F., Zhang, R.-Y., Yu, Z.-H., Liu, S., Wu, L., Gunawan, A. M., Lane, B. S., Mali, R. S., Li, X., Chan, R. J., Kapur, R., Wells, C. D., and Zhang, Z.-Y. “Therapeutic potential of targeting oncogenic SHP2 phosphatase”, J. Med. Chem.57, 6594-6609 (2014).
He, R., Yu, Z.-H., Zhang, R.-Y., Wu, L., Gunawan, A., Lane, B. S., Shim, J. S., Zeng, L.-F., He, Y., Chen, L., Wells, C. D., Liu, J. O., and Zhang, Z.-Y. “Exploring the existing drug space for novel pTyr mimetic and SHP2 inhibitors”, ACS Med. Chem. Lett. 6, 782-786 (2015).
Bunda, S., Burrell, K., Heir, P., Zeng, L.-F., Alamsahebpour, A., Kano, Y., Raught, B., Zhang, Z.-Y., Zadeh, G., and Ohh, M. “Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis”, Nature Communications 6, 8859 (2015).
He, R., Yu, Z.-H., Zhang, R.-Y., Wu, L., Gunawan, A. M., and Zhang, Z.-Y. “Cefsulodin inspired potent and selective inhibitors of mPTPB, a virulent phosphatase from Mycobacterium tuberculosis”, ACS Med. Chem. Lett. 6, 1231-1235 (2015).
Dutta, N. K., He, R., Pinn, M. L., He, Y., Burrows, F., Zhang, Z.-Y., and Karakousis, P. C. “Mycobacterial protein tyrosine phosphatases A and B inhibitors augment the bactericidal activity of standard anti-tuberculosis regimen”, ACS Infectious Diseases 2, 231-239 (2016).
Wang, Y., Mizui, M., Zeng, L-F., Bronson, R., Finnell, M., Terhorst, C., Kyttaris, V. C., Tsokos, G. C., Zhang, Z.-Y., and Kontaridis, M. “Inhibition of SHP2 Ameliorates the Pathogenesis of Systemic Lupus Erythematosus”, J. Clin. Invest. 126, 2077-2092 (2016).
Bai, Y., Yu, Z., Liu, S., Zhang, L., Zhang, R.-Y., Zeng, L.-F., Zhang, S., and Zhang, Z.-Y. “Novel anticancer agents based on targeting the trimer interface of the PRL phosphatase”, Cancer Res. 76, 4805-4815 (2016).
Zhang, R.-Y., Yu, Z.-H., Zeng, L.-F., Zhang, S., Bai, Y., Miao, J., Chen, L., Xie, J. and Zhang, Z.-Y. “SHP2 phosphatase as a novel target for melanoma treatment”, Oncotarget 7, 73817-73829 (2016).
Bai, Y., Zhou, H.-M., Zhang, L., Dong, Y., Zeng, Q., Shou, W., and Zhang, Z.-Y. “Role of Phosphatase of Regenerating Liver 1 (PRL-1) in spermatogenesis”, Scientific Reports 6, 34211 (2016).
He, R., Wang, J., Yu, Z.-H., Zhang, R.-Y., Liu, S., Wu, L., and Zhang, Z.-Y. “Inhibition of low molecular weight protein tyrosine phosphatase by an induced-fit mechanism”, J. Med. Chem. 59, 9094-9106 (2016).
Kobayashi, M., Bai, Y., Chen, S., Gao, R., Yao, C., Cai, W., Cardoso, A. A., Croop, J., Zhang, Z.-Y., and Liu, Y. “Phosphatase PRL2 promotes oncogenic Notch1-induced T cell leukemia”, Leukemia 31, 751-754 (2017).
Zhang, Z.-Y. “Drugging the undruggable: therapeutic potential of targeting protein tyrosine phosphatases”, Acc. Chem. Res. 50, 122-129 (2017).
Kobayashi, M., Nabinger, S., Bai, Y., Yoshimoto, M., Gao, R., Chen, S., Yao, C., Dong, Y., Zhang, L., Rodriguez, S., Yashiro-Ohtani, Y., Pear, W. S., Carlesso, N., Yoder, M. C., Kapur, R., Kaplan, M. H., Lacorazza, H. D., Zhang, Z.-Y., and Liu, Y. “Protein tyrosine phosphatase PRL2 mediates Notch and Kit signals in early T cell progenitors”, Stem Cells 35, 1053-1064 (2017).
Kobayashi, M., Chen, S., Bai, Y., Yao, C., Gao, R., Sun, X.-J., Mu, C., Twiggs, T., Yu, Z., Boswell, H. S., Yoder, M., Kapur, R., Mulloy, J., Zhang, Z.-Y., and Liu, Y. “Phosphatase PRL2 promotes AML1-ETO-induced acute myeloid leukemia”, Leukemia 31, 1453-1457 (2017).
Ruddraraju, K. V. and Zhang, Z.-Y. “Covalent inhibition of protein tyrosine phosphatases”, Molecular BioSystems 13, 1257-1279 (2017).
Yu, Z.-H., and Zhang, Z.-Y. “Regulatory mechanisms and novel therapeutic targeting strategies for protein tyrosine phosphatases” Chemical Reviews 117, in press (2017).
Sacchetti, C., Bai, Y., Stanford, S. M., Piera-Velazquez, S., Vladimir, C., Kiosses, W. B., Boin, F., Jimenez, S. A., Zhang, Z.-Y., and Bottini, N. “PTP4A1 phosphatase is overexpressed in systemic sclerosis fibroblasts and promotes TGFb signaling”, Nature Communications, in press (2017).
Yamashita, N., Joshi, R., Zhang, S., Zhang, Z.-Y., and Kuruvilla, R. “Phospho-regulation of soma-to-axon transcytosis of neurotrophin receptors”, Dev. Cell, in press (2017).