Faculty

Currently Accepting Students

Chemical Biology and Therapeutic Targeting of Protein Tyrosine Phosphatases: From Target Identification/Validation to Hit/Lead Generation and Preclinical Evaluation

Our research spans the disciplines of chemistry and biology with an emphasis on protein tyrosine phosphatases (PTPs), enzymes that remove phosphoryl groups from tyrosine phosphorylated proteins and regulate a plethora of cellular processes, including growth, differentiation, metabolism, and the immune response. Abnormal PTP activity leads to aberrant cellular signaling, which is linked to the development of cancer, diabetes/obesity, neurodegenerative and autoimmune disorders, and infectious diseases. Consequently, there is heightened interest to control disease progression at the level of PTPs.

Using state-of-the-art molecular, cellular and mouse genetic techniques (e.g. CRISPR gene editing, siRNA silencing, and gene knockout), we seek to fully characterize the >100 members of the PTP family and understand how PTP activity is regulated to modulate cellular signaling and how PTP malfunction causes diseases. To promote therapeutic application of drugging the PTPs as a target class, we employ fragment-based, and structure-guided medicinal chemistry to develop potent and selective chemical probes (orthosteric and allosteric inhibitors, covalent modifiers, and PROTAC-based small molecule degraders) for PTP functional interrogation, target validation, and therapeutic development. Current efforts aim to advance our target validation and lead generation paradigm and to create a ‘PTP-based drug discovery platform’ that will ultimately impact the therapeutic portfolio of tomorrow.

Our research program is multifaceted and incorporates both established and emerging technologies, across disciplines. Students have ample opportunity to interact with a highly interactive, collaborative and multi-disciplinary group of individuals with expertise ranging from biochemistry, cell biology, mouse genetics, structural biology, mass spectrometry, organic synthesis, medicinal chemistry, chemical biology and in vivo pharmacology.

Complete List of Lab Publications and Google Scholar Citations (https://www.zyzhanglab.com/publications)

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).

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).

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, 20538-20548 (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”, J. Med. Chem. 63, 9212-9227 (2020).

Zhu, G., Xie, J., Kong, W., Xie, J., Li, Y., Du, L., Zheng, Q., Sun, L., 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 underlies MAPK hyperactivation”, Cell 183, 490-502(2020).

Chen, H., Libring, S., Ruddraraju, K. V., Miao, J., Solorio, L., Zhang, Z.-Y., and Wendt, M. K. “SHP2 is a multifunctional therapeutic target in drug resistant metastatic breast cancer”, Oncogene 39, 7166-7180 (2020).

Ruddraraju, K. V., Aggarwal, D., and Zhang, Z.-Y. “Therapeutic Targeting of Protein Tyrosine Phosphatases from Mycobacterium tuberculosis”, Microorganisms 9, 14 (2021).

Ho, W. J., Croessmann, S., Lin, J., Phyo, Z., Charmsaz, S., Danilova, L., Mohan, A., Gross, N., Chen, F., Dong J., Aggarwal, D., Bai, Y., Wang, J., He, J., Leatherman, J., Yarchoan, M., Armstrong, T., Zaidi, N., Fertig, E. J., Denny, J. C., Park, B. H.,* Zhang, Z.-Y.,* and Jaffee, E. M.* “Systemic inhibition of PTPN22 augments anticancer immunity”, J. Clin. Invest. 131, e146950 (2021).

Krabill, A. D. and Zhang, Z.-Y. “Functional interrogation and therapeutic targeting of protein tyrosine phosphatases”, Biochemical Society Transactions 49, 1723-1734 (2021).

Yu, G., Bai, Y., Li, K., Amarasinghe, O., Jiang, W., and Zhang, Z.-Y. “Cryo-Electron Microscopy Structures of VCP/p97 Reveal a New Mechanism of Oligomerization Regulation”, iScience 24, 103310 (2021).

Jassim, B. A., Lin, J., and Zhang, Z.-Y. “PTPN22: Structure, Function, and Developments in Inhibitor Discovery with Applications for Immunotherapy”, Expert Opinion on Drug Discovery 17, 825-837 (2022).

Zhu, P., Wu, X., Zhang, R.-Y., Hsu, C.-C., Zhang, Z.-Y., and Tao, W. A. “An integrated proteomic strategy to identify SHP2 substrates”, Journal of Proteome Research 21, 2515-2525 (2022).

He, R., Wang, J., Yu, Z.-H., Moyers, J. S., Michael, M. D., Durham, T. B., Cramer, J. W., Qian, Y., Lin, A., Wu, L., Noinaj, N., Barrett, D. G., and Zhang, Z.-Y. “Structure Based Design of Active Site-Directed, Highly Potent, Selective, and Orally Bioavailable LMW-PTP Inhibitors”, J. Med. Chem. 65, 13892-13909 (2022).

Wang, X., Yang, C., Wang, X., Miao, J., Chen, W., Zhou, Y., Xu, Y., An, Y., Cheng, A., Ye, W., Chen, M., Song, D., Yuan, X., Wang, J., Qian, P., Wu, A. R., Zhang, Z.-Y., and Liu, K. “Driving Axon Regeneration by Orchestrating Neuronal and Non-neuronal Innate Immune Responses via the IFNγ-cGAS-STING Axis”, Neuron 111, 236-255 (2023).

Chen, H.; Bai, Y., Kobayashi, M., Xiao, S., Cai, W., Barajas, S., Chen, S., Miao, J., Nguele Meke, F., Vemula, S., Ropa, J. P., Croop, J. M., Boswell, H. S., Wan, J., Jia, Y., Liu, H., Li, L. S., Altman, J. K., Eklund, E. A., Ji, P., Tong, W., Band, H., Huang, D. T., Platanias, L. C., Zhang, Z.-Y.,* and Liu, Y.* “PRL2 phosphatase enhances oncogenic FLT3 signaling via dephosphorylation of the E3 ubiquitin ligase CBL at tyrosine 371”, Blood 141, 244-259 (2023)

Bai, Y., Yu, G., Zhou, H.-M., Amarasinghe, O., Zhou, Y., Zhu, P., Li, Q., Zhang, L., Nguele Meke, F., Miao, Y., Chapman, E., Tao, W. A., and Zhang, Z.-Y. “PTP4A2 promotes lysophagy by dephosphorylation of VCP/p97 at Tyr805”, Autophagy 19, 1562-1581 (2023).

Dong, J., Miao, J., Miao, Y. Qu, Z., Zhang, S., Zhu, P., Wiede, F., Jassim, B. A., Bai, Y., Nguyen, Q., Lin, J., Chen, L., Tiganis, T., Tao, W. A., and Zhang, Z.-Y. “Small Molecule Degraders of Protein Tyrosine Phosphatase 1B and T-Cell Protein Tyrosine Phosphatase for Cancer Immunotherapy”, Angew. Chem. Int. Ed. 62, e202303818 (2023).

Carlock, C., Bai, Y., Paige-Hood, A., Li, Q., Nguele Meke, F., and Zhang, Z.-Y. “PRL2 inhibition elevates PTEN proteinand ameliorates progression of acute myeloid leukemia”, JCI Insight 8, e170065 (2023).

Miao, J., Bai, Y., Miao, Y., Qu, Z., Dong, J., Zhang, R.-Y., Aggarwal, D., Jassim, B. A., Nguyen, Q. and Zhang, Z.-Y. “Discovery of a SHP2 degrader with in vivo anti-tumor activity”, Molecules 28, 6947 (2023).

Miao, J. Dong, J., Miao, Y., Bai, Y., Qu, Z., Jassim, B. A., Huang, B., Nguyen, Q., Ma, Y., Murray, A. A., Li, J., Low, P. S., and Zhang, Z.-Y. “Discovery of a selective TC-PTP degrader for cancer immunotherapy”, Chemical Science 14, 12606-12614 (2023)

Chen, H., Bai, Y., Kobayashi, M., Xiao, S., Barajas, S., Cai, W., Chen, S., Miao, J., Nguele Meke, F., Yao, C., Yang, Y., Strube, K., Satchivi, O., Sun, J., Rönnstrand, L., Croop, J. M., Boswell, H. S., Jia, Y., Liu, H., Li, L. S., Altman, J. K., Eklund, E. A., Sukhanova, M., Ji, P., Tong, W., Band, H., Huang, D. T., Platanias, L. C., Zhang, Z.-Y.,* and Liu, Y.* “PRL2 phosphatase promotes oncogenic KIT signaling in leukemia cells through modulating CBL phosphorylation”, Molecular Cancer Research 22, 94-103 (2024).

Nguele Meke, F., Bai, Y., Ruiz-Avila, D., Carlock, C., Ayub, J., Miao, J., Hu, Y., Li, Q., and Zhang, Z. Y. “Inhibition of PRL2 upregulates PTEN and attenuates tumor growth in Tp53-deficient sarcoma and lymphoma mouse models”, Cancer Research Communications 4, 5-17 (2024).

Qu, Z., Krabill, A. D. and Zhang, Z.-Y. “High throughput discovery and characterization of covalent inhibitors for protein tyrosine phosphatases”, Methods in Molecular Biology 2743, 301-316 (2024).

Qu, Z., Dong, J., and Zhang, Z.-Y. “Protein tyrosine phosphatases as emerging targets for cancer immunotherapy”, The British Journal of Pharmacology 180, in press (2024).

Miao, J. and Zhang, Z.-Y. “Drugging Protein Tyrosine Phosphatases through Targeted Protein Degradation”, ChemMedChem 18, in press (2024).