Distinguished Professor of Medicinal Chemistry
Robert C. and Charlotte P. Anderson Chair in Pharmacology
Director, Purdue Institute for Drug Discovery
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: From Target Identification/Validation to Hit/Lead Generation and Preclinical Evaluation
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.
A. M. Ovini Amarasinghe (Graduate Student)
Yunpeng Bai (Research Associate)
Colin Carlock (Graduate Student)
Jiajun Dong (Graduate Student)
Vikram Gaddam (Post-Doctoral Research Associate)
Brenson Austin Jassim (Graduate Student)
Aaron D. Krabill (Post-Doctoral Research Assistant)
Jianping Lin (Post-Doctoral Research Associate)
Jinmin Miao (Post-Doctoral Research Associate)
Yiming Miao (Graduate Student)
Frederick Georges Bernard Nguele Meke (Graduate Student)
Zihan Qu (Graduate Student)
Paul Joseph Tholath (Graduate Student)
Guimei Yu (Post-Doctoral Research Associate)
Ruo-Yu Zhang (Research Associate)
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).
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).
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 Medicinal Chemistry Letter 6, 782-786 (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).
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).
Complete List of Publications for Dr. Zhang and Google Scholar Citations (https://www.chem.purdue.edu/zhang/publications.html)