Zhong-Yin Zhang

Active Mentor - currently hosting PULSe students for laboratory rotations and recruiting PULSe students into the laboratory; serves on preliminary exam committees

Current Research Interests:

Structure/Function, Signaling Mechanism, and Therapeutic Targeting of Protein Tyrosine Phosphatases Aberrant cellular signaling stemming from altered protein tyrosine phosphorylation is a major contributing factor to human diseases. Consequently, anomalous cellular events driven by defective tyrosine phosphorylation afford tremendous opportunities for targeted intervention. This is evident by the abundance of kinase-based therapeutics that have become important cancer treatment modalities. Given the reversible nature of protein tyrosine phosphorylation, it is conceivable that disease progression could be halted by modulating the activity of protein tyrosine phosphatases (PTPs). However, despite increasing attention to the PTPs, they still remain largely an underexploited target class. Among factors that contribute to the difficulty of PTP-based drug discovery are lack of detailed understanding of how PTP malfunction causes diseases and insufficient target validation. In addition, the PTPs are exceptionally challenging targets for the development of potent and selective small molecule inhibitors 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 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.

Selected Publications:

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., 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).

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).

Zhang, Z.-Y. “Drugging the undruggable: therapeutic potential of targeting protein tyrosine phosphatases”, Acc. Chem. Res. 50, 122-129 (2017).

Kobayashi, M., Chen, S., Bai, Y., Yao, C., Gao, R., Sun, X.-J., Mu, C., Twiggs, T., Yu, Z. H., Boswell, H. S., Yoder, M. C., Kapur, R., Mulloy, J. C., Zhang, Z.-Y., and Liu, Y. “Phosphatase PRL2 promotes AML1-ETO-induced acute myeloid leukemia”, Leukemia 31 1453-1457 (2017).

Frankson, R., Yu, Z.-H., Bai, Y., Li, Q., Zhang, R.-Y., Zhang, Z.-Y. “Therapeutic targeting of oncogenic tyrosine phosphatases”, Cancer Research 77, 5701-5705 (2017).

Yu, Z.-H., and Zhang, Z.-Y. “Regulatory mechanisms and novel therapeutic targeting strategies for protein tyrosine phosphatases” Chemical Reviews 118, 1069-1091 (2018).

Zhang, R.-Y., Yu, Z.-H., Chen, L., Walls, C. D., Zhang, S., Wu, L., and Zhang, Z.-Y. “Mechanistic insights explain the transforming potential of the T507K substitution in the protein tyrosine phosphatase SHP2”, J. Biol. Chem. 295, 6187-6201 (2020).

Li, Q., Bai, Y., Lyle, L. T., Yu, G., Amarasinghe, O., Nguele Meke, F., Carlock, C., and Zhang, Z.-Y. “Mechanism of PRL2 phosphatase mediated PTEN degradation and tumorigenesis”, Proc. Natl. Acad. Sci. USA 117, in press (2020).

Zhu, G., Xie, J., Kong, W., Xie, J., Li, Y., Du, L., Zheng, Q., Lin, S., Guan, M., Li, H., Zhu, T., He, H., Liu, Z., Xia, X., Kan, C., Tao, Y., Shen, H. C., Li, D., Wang, S., Yu, Y., Yu, Z.-H., Zhang, Z.-Y., Liu, C., and Zhu, J. “Phase separation of disease-associated SHP2 mutants regulates protein tyrosine phosphatase activity underlying pathological MAPK hyperactivation”, Cell 182, in press (2020).

Ruddraraju, K. V., Aggarwal, D., Niu, C., Baker, E. A., Zhang, R.-Y., Wu, L., and Zhang, Z.-Y. “Highly Potent and Selective N-aryl Oxamic Acid Based Inhibitors for Mycobacterium Tuberculosis Protein Tyrosine Phosphatase B (mPTPB)”, J. Med. Chem. 63, in press (2020).