Zhengyu Wang, PhD

Assistant Professor/Research

Personal Statement:

My current research is focused on the following areas:

1) Rational Design and Synthesis of Poly-Pharmacological Agents for Targeted Therapy:

The core of cancer research has traditionally revolved around the discovery and development of small molecules that disrupt the function of specific abnormal proteins driving cancer progression. However, achieving the desired anti-tumor activity both in vitro and in vivo often necessitates administering targeted therapies at or near the maximum tolerated dose. To enhance therapeutic efficacy and widen the therapeutic window, it is beneficial to dial in the inhibitory activities on other pathways or targets. In contrast to single-target agents that pursue deep inhibition on individual pathways or targets, a rational approach involves designing poly-pharmacological agents with balanced inhibitory profiles across multiple pathways or targets. These Poly-Pharmacological Agents can potentially reduce toxicity while capitalizing on the benefits of synergistic combination therapy. Furthermore, poly-pharmacological agents may also offer reduced risk of resistance by simultaneously inhibiting multiple pathways.

2) Discovery and Development of Small Molecules for Catalytic Degradation of Targeted Proteins:

Conventional drugs often require high concentrations to maintain sufficient target occupancy for therapeutic effects (occupancy-driven pharmacology). However, high drug concentrations are associated with off-target effects. Catalytic degradation of targeted proteins through the proteasomal and lysosomal pathways can address many limitations of small molecule inhibitors. A prominent chemical modality for catalytic degradation is the Proteolysis Targeting Chimera (PROTAC), comprising two ligands connected by a linker. One ligand recruits and binds a protein of interest (POI), while the other recruits and binds an E3 ubiquitin ligase. With only a brief interaction with the POI, PROTAC bridges the POI and E3 ligase ligand, leading to ubiquitination and subsequent degradation of the POI (event-driven pharmacology). Following the destruction of the POI, PROTAC can carry on another cycle of POI degradation in a catalytic manner. As the efficacy of PROTAC is not constrained by equilibrium occupancy, it can achieve sustained inhibition of targets and downstream signaling at lower drug concentrations. Additionally, catalytic degradation can address conformational changes in proteins due to mutations and target scaffold functions, a capability often lacking in traditional inhibition methods.

Education

B.S. - Chongqing Medical University, Chongqing, China
Joint PhD and MS Programs - Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Ph.D., M.S. - Medical Chemistry, China Pharmaceutical University, Nanjing, China
Postdoctoral Fellowship - University of Arkansas for Medical Sciences, Little Rock, Arkansas

Research

Drug discovery
Inhibitor
Targeted protein degraders
Organic synthesis Drug delivery Medicinal chemistry Chemical biology

Awards & Accomplishments

Cui R., Li H. Y., Wang Z., and Shao J., Mi-2beta inhibtor as an immunotherapy agents, [P] US17696610

Li H., Wang Z., Qin Z., and Henry Wong, Development of potent dual HDAC/BRD4 inhibitors [P].(WO/2024/123929)

Publications

Wang Z.#, Pan B.-S.#, Manne R. J.#, Chen J.#, Lv D., Wang M., Tran P., Weldemichael T. G., Yan W., Zhou H., Martinez G. M., Shao J., Hsu C.-C, Hromas, R., Zhou D., Qin Z., Lin H.-K., Li H.-Y. CD36-mediated endocytosis of proteolysis-targeting chimeras. Cell, 2025, DOI: 10.1016/j.cell.2025.03.036

Tran P, Moccia M., Wang X., Brescia A., Federico G., Gunaganti N., Wang Z., Yang M., Wang M., Jabali B., Yan W., Frett B., Santoro M., Carlomagno F., and Li H. Discovery of N-(3-fluorophenyl)-2-(4-((7-(1-methyl-1H-pyrazol -4-yl)quinazolin-4-yl)amino)phenyl)acetamide as the first orally active selective aurora kinase B inhibitor. Eur. J. Med. Chem., 2025, 117735. DOI: https://doi.org/10.1016/j.ejmech.2025.117735.

Ran K., Huang J.-H., Li Y., Zhang Y., Hu H., Wang Z., Tang D.-Y., Li H.-Y., Xu Z.-G., Chen Z.-Z. Design, synthesis, and biological evaluation of thieno[3,2-d]pyrimidine derivatives as the first bifunctional PI3Kδ isoform selective/bromodomain and extra-terminal inhibitors. J. Med. Chem., 2025, 68, 3, 3260-3281. DOI: 10.1021/acs.jmedchem.4c02478

Li C.#, Wang Z.#, Yao L.#, Lin X., Jian Y., Li Y., Zhang J., Shao J., Tran P. D., Hagman J. R., Cao M., Cong Y., Li H.-Y., Goding C. R., Xu Z.-X., Liao X., Miao X., Cui R. Mi-2β promotes immune evasion in melanoma by activating EZH2 methylation. Nat. Commun., 2024, 15(1): 2163. DOI: 10.1038/s41467-024-46422-5

Lakkaniga N. R.#, Wang Z.#, Xiao Y.#, Kharbanda A., Lan L., and Li H. Revisiting Aurora kinase B: a promising therapeutic target for cancer therapy. Med. Res. Rev., 2023. DOI: 10.1002/med.21994

Chen T., Xu Z. G., Luo J., Manne R. K., Wang Z., Hsu C. C., Pan B. S., Cai Z., Tsai P. J., Tsai Y., S., Chen Z. Z., Li H. Y., and Lin H. K., (2023) NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance, Cell Metabolism, 35(10), 1782-1798.e8.

Chen J., Wang Z., Phuc T., Xu Z., Yang D., Chen Z., Lin Z., Kendrick S., Dai L., Li H. Y., and Qin Z., (2023) Oncolytic strategy using new bifunctional HDACs/BRD4 inhibitors against virus-associated lymphomas, Plos Pathogens, 19(1), e1011089.

Yan Y., Shao J., Ding D., Phuc T., Yan W., Wang Z., Li H. Y., and Huang H., (2022) 3-Aminophthalic acid, a new cereblon ligand for targeted protein degradation by O’PROTAC, Chemical Communications, 58(14), 2383-2386.

Zhu B., Wang Z., Yao L., Lin X., Zhang J., Li X., Hagman J. R., Shao J., Tran P. D., Cao M., Zhang J., Goding C. R., Liao X., Li H., Cao P., Miao X., and Cui R. Mi-2β-targeting inhibition induces immunnotherapy response in melanoma [J]. BioRxiv preprint, 2021. DOI: 10.21203/rs.3.rs-118153/v1

Xu X., Wang W., Wang Z., Lv J., Xu X., Xu J., Yang J., Zhu X., Lu J., Duan W., Huang X., Wang J., Zhou J., and Shen X., (2020) DW14006 as a direct AMPKα activator ameliorates diabetic peripheral neuropathy in mice, Diabetes, 69(9), 1974-1988.

Lv J., Wang W., Zhu X., Xu X., Yan Q., Lu J., Shi X., Wang Z., Zhou J., Huang X., Wang J., Duan W., and Shen X., (2020) DW14006 as a direct AMPKα1 activator improves pathology of AD model mice by regulating microglial phagocytosis and neuroinflammation, Brain, Behavior, and Immunity, 90, 55-69.

Zhang D., Burdette B. E., Wang Z., Karn K., Li H. Y., Schramm V. L., Tyler P. C., Evans G. B., and Wang S., (2020) Transition state analogues enhanced by fragment-based structural analysis: bacterial methylthioadenosine nucleosidases, Biochemistry, 59(7), 831-835.

Storey A. J., Naceanceno K. S., Lan R. S., Washam C. L., Orr L. M., Mackintosh S. G., Tackett A. J., Edmondson R. D., Wang Z., Li H., Frett B., Kendrick S., and Byrum S. D. (2020) ProteoViz: a tool for the analysis and interactive visualization of phosphoproteomics data, Mol Omics 16, 316-326.

Zhang H., Wang Z., Duan W. Zhou J., and Zhang H. Progress in AMPK activators as the treatment of Alzheimer’s disease through autophagy regulation. Prog. Pharm. Sci., 2017, 41(6): 411-418.

Wang Z., Shi X., Zhang H., Yu L., Cheng Y., Zhang H., Zhang H., Zhou J., Chen J., Shen X., and Duan W., (2017) Discovery of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific glucokinase activators: Design, synthesis, and biological evaluation, Eur J Med Chem 139, 128-152.

Yan W., Huang Z., Wang Z., Cao S., Tong L., Zhang T., Wang C., Zhou L., Ding J., Luo C., Zhou J., Xie H., and Duan W. Discovery of 1, 3-diaryl-pyridones as potent VEGFR-2 inhibitors: design, synthesis, and biological evaluation. Chem. Biol. Drug. Des., 2016, 87(5): 694-703. DOI: 10.1111/cbdd.12703

Wang Z., Duan W., Zhou J., and Zhang H. Small molecule glucokinase activators [J]. Prog. Pharm. Sci., 2014, 38(6): 438-445.

Han Y., Wang B., Wang Z., Zhang Y., Yang L, Zhou J., and Zhang H. Recent research in progress in pharmacological effects of glycyrrhizic acid. Chin. J. New. Drugs, 2012, 21(21): 2499-2505.