About

Guangrong Zheng, Ph.D., is a professor in the department of medicinal chemistry at the University of Florida College of Pharmacy. He received his B.S. in medicinal chemistry from Fudan University and his Ph.D. in synthetic organic chemistry from Shanghai Institute of Materia Medica. He completed postdoctoral training in drug design and discovery at the University of Kentucky College of Pharmacy. Prior to joining UF in March 2018, he was a faculty member at the University of Arkansas for Medical Sciences College of Pharmacy. His research focuses on the design, synthesis, and structure-activity relationship study of both synthetically derived and natural product-based compounds for potential therapeutic uses or as molecular probes for biochemical and pharmacological research. His lab also develops efficient synthetic methodologies and strategies to facilitate rapid construction of compound libraries. Current projects include developing small molecules for targeted protein degradation as potential cancer treatments, senolytic agents for age-related diseases, and radioprotective agents to improve cancer radiotherapy outcomes or serve as radiation counter-measures.

Research topics

• Pharmacology
• Biochemistry
• Chemistry
• Cell biology
• Biology
• Medicine
• Internal medicine
• Cancer research
• Computational biology
• Genetics
• Immunology

Selected publications

• Tumor cell membrane camouflaged liposomal pharmaceuticals for cascade catalysis‐driven redox modulation and synergistic ROS/RNS antitumor therapy

  View · 2026-02-04

  articleOpen access1st author

  Abstract The antioxidant defense system (ADS) within the tumor microenvironment restricts the efficacy of reactive oxygen species (ROS) based therapies by conferring intrinsic redox tolerance. To overcome this limitation, we develop a tumor cell membrane camouflaged liposomal nanoplatform (C‐MLip@LA) that modulates the ADS to enhance tumor‐targeted therapy through a synergistic reactive oxygen/nitrogen species (ROS/RNS) cascade. The system encapsulates L‐arginine (LA) as the core, anchors MnO 2 nanoparticles on the liposomal surface, and is cloaked with homologous tumor cell membranes, thereby enabling tumor‐specific recognition and immune evasion. C‐MLip@LA disassembles after cellular internalization, where MnO 2 depletes intracellular glutathione (GSH) and is reduced to Mn 2 + , thereby elevating ROS levels and enabling T 1 ‐weighted magnetic resonance imaging. Concurrently, the released LA reacts with endogenous H 2 O 2 to generate nitric oxide (NO). The interplay between NO and ROS initiates a cascade reaction that produces highly cytotoxic peroxynitrite, thereby amplifying immunogenic cell death and leading to pronounced tumor growth inhibition in a CT‐2A tumor model. Collectively, this work presents a biomimetic nanoplatform for redox‐modulated cancer therapy with integrated diagnostic and immunomodulatory functions.

  PublisherDOI

• Unveiling BCL-xL-specific PROTAC Efficiency and Dissociation Mechanisms Using Native Mass Spectrometry

  ChemRxiv · 2025-09-23 · 1 citations

  article

  Overexpression of anti-apoptotic proteins such as BCL-xL is a hallmark of various cancers and a major driver of resistance to conventional chemotherapies. While small-molecule BCL-xL inhibitors have shown promising outcomes, their clinical use is hindered by dose-limiting toxicities, especially thrombocytopenia. Proteolysis-targeting chimeras (PROTACs) offer a promising alternative by promoting selective degradation of target proteins via the ubiquitin-proteasome system, thereby reducing off-target effects associated with small molecule inhibitors. However, rational design and optimization of PROTACs remain challenging due to the need to balance simultaneous interactions with both an E3 ubiquitin ligase and the target protein. Here we employ native mass spectrometry (MS) as a rapid, label-free platform to screen and characterize the formation and stability of ternary complexes between BCL-xL, VHL E3 ligase complex (VCB), and various targeting PROTACs. Native MS enables direct detection of binary BCL-xL●PROTAC and ternary BCL-xL●PROTAC●VCB complexes and provides semi-quantitative insights into PROTAC affinity and cooperativity with both binding partners. Furthermore, we explore the dissociation pathways of these complexes in the gas phase using collision-induced dissociation (CID) and ultraviolet photodissociation (UVPD), revealing distinct fragmentation and subunit release patterns that reflect the structural organization and gas-phase stability of the complexes. Variable-temperature ESI-MS (vT-ESI) further allows assessment of thermal stabilities of the complexes in solution. Together, our study demonstrates the power of native MS to both screen and mechanistically characterize PROTAC-induced ternary complex formation.

  PublisherDOI

• Efficacy of a novel BCL-xL degrader, DT2216, in preclinical models of <i>JAK2</i>-mutated post-MPN AML

  Blood · 2025-03-31 · 20 citations

  articleOpen access

  ABSTRACT: Acute myeloid leukemia (AML) that evolves from myeloproliferative neoplasm (MPN) is known as post-MPN AML. Current treatments do not significantly extend survival beyond 12 months. B-cell lymphoma-extra large (BCL-xL) has been found to be overexpressed in leucocytes from patients with MPN, making it a potential therapeutic target. We investigated the role of BCL-xL in post-MPN AML and tested the efficacy of DT2216, a platelet-sparing BCL-xL proteolysis-targeting chimera, in preclinical models of post-MPN AML. We found that BCL2L1, the gene encoding BCL-xL, is expressed at higher levels in patients with post-MPN AML than in those with de novo AML. Single-cell multiomics analysis revealed that leukemia cells harboring both MPN-driver and TP53 mutations exhibited higher BCL2L1 expression and elevated scores for leukemia stem cell, megakaryocyte development, and erythroid progenitor than wild-type cells. BH3 profiling confirmed a strong dependence on BCL-xL in post-MPN AML cells. DT2216 alone, or in combination with standard AML/MPN therapies, effectively degraded BCL-xL, reduced the apoptotic threshold, and induced apoptosis in post-MPN AML cells. DT2216 effectively eliminated viable cells in JAK2-mutant AML cell lines, induced pluripotent stem cell-derived hematopoietic progenitor cells, primary samples, and reduced tumor burden in cell line-derived xenograft model in vivo by degrading BCL-xL. DT2216, either as a single agent or in combination with azacytidine, effectively inhibited the clonogenic potential of CD34+ leukemia cells from patients with post-MPN AML. In summary, our data indicate that the survival of post-MPN AML is BCL-xL dependent, and DT2216 may offer therapeutic advantage in this high-risk leukemia subset with limited treatment options.

  PublisherOA PDFDOI

• Discovery of Dual BCL-xL/BCL-w Degraders by Exploiting the Bis(sulfonyl)benzene Ring of ABT-263 as a Linkage Vector

  Journal of Medicinal Chemistry · 2025-08-29 · 2 citations

  articleSenior authorCorresponding

  Targeting antiapoptotic proteins BCL-xL, BCL-2, and BCL-w has been extensively investigated for cancer treatment. However, robust inhibition of BCL-xL by conventional inhibitors, such as ABT-263, causes thrombocytopenia, a notable drawback that limits the clinical utility of this strategy. To overcome this on-target toxicity, BCL-xL-selective and BCL-xL/BCL-2 dual-targeting proteolysis targeting chimeras (PROTACs) have been developed as alternative therapeutic strategies. In this study, we report a new generation of ABT-263-based PROTACs designed to leverage a novel solvent-exposed region on the bis(sulfonyl)benzene ring of ABT-263, made accessible through regioselective electrophilic aromatic bromination. The lead compounds, 44 and 46, demonstrated effective degradation of BCL-xL and, unexpectedly, degraded BCL-w, while sparing BCL-2. With further optimization, these BCL-xL and BCL-w dual-targeting PROTACs hold great promise as safer, more effective anticancer agents against BCL-xL and BCL-w codependent cancers.

  PublisherDOI

• Quiescent OXPHOS-High Triple-Negative Breast Cancer Cells That Persist After Chemotherapy Depend on BCL-XL for Survival

  Cells · 2025-10-08

  articleOpen access

  The persistent residual tumor cells that survive after chemotherapy are a major cause of treatment failure, but their survival mechanisms remain largely elusive. These cancer cells are typically characterized by a quiescent state with suppressed activity of MYC and MTOR. We observed that the MYC-suppressed persistent triple-negative breast cancer (TNBC) cells are metabolically flexible and can upregulate mitochondrial oxidative phosphorylation (OXPHOS) genes and respiratory function ("OXPHOS-high" cell state) in response to DNA-damaging anthracyclines such as doxorubicin, but not to taxanes. The elevated biomass and respiratory function of mitochondria in OXPHOS-high persistent cancer cells were associated with mitochondrial elongation and remodeling, suggestive of increased mitochondrial fusion. A genome-wide CRISPR editing screen in doxorubicin-persistent OXPHOS-high TNBC cells revealed the BCL-XL gene as the top survival dependency in these quiescent tumor cells, but not in their untreated proliferating counterparts. Quiescent OXPHOS-high TNBC cells were highly sensitive to BCL-XL inhibitors, but not to inhibitors of BCL2 and MCL1. Interestingly, inhibition of BCL-XL in doxorubicin-persistent OXPHOS-high TNBC cells rapidly abrogated mitochondrial elongation and respiratory function, followed by caspase 3/7 activation and cell death. The platelet-sparing proteolysis-targeted chimera (PROTAC) BCL-XL degrader DT2216 enhanced the efficacy of doxorubicin against TNBC xenografts in vivo without induction of thrombocytopenia that is often observed with the first-generation BCL-XL inhibitors, supporting the development of this combinatorial treatment strategy for eliminating dormant tumor cells that persist after treatment with anthracycline-based chemotherapy.

  PublisherOA PDFDOI

• Escherichia coli combination with PD-1 blockade synergistically enhances immunotherapy in glioblastoma multiforme by regulating the immune cells

  Journal of Translational Medicine · 2025-02-07 · 1 citations

  articleOpen access

  BACKGROUND: Glioblastoma multiforme (GBM) is the most common and aggressive primary intracranial malignancy. It is characterized by insufficient infiltration of anti-tumor T lymphocytes within the tumor microenvironment (TME), rendering it an "immune cold" disease. This immune deficiency results in poor responses to immune checkpoint blockade (ICB) therapies. Recent studies have demonstrated that bacteria can proliferate within tumors and activate immune responses. Therefore, in this study, we employed Escherichia coli (E. coli) in combination with anti-PD-1 antibodies to treat GBM, with the aim of exploring the immune-activating potential of E. coli in GBM and its synergistic effect on anti-PD-1 therapy. METHODS: The E. coli and anti-PD-1 antibody therapy were administered intravenously and intraperitoneally, respectively. Complete blood cell count, blood biochemical analysis, hematoxylin and eosin (H&E) staining, and agar plate culture were employed to evaluate the biosafety and tumor-targeting capability of E. coli. ELISA kits were used to detect innate immune cytokines. Flow cytometry and immunofluorescence staining were used to investigate T cells. Tumor volume of tumor-bearing mice was recorded to evaluate the combined treatment efficacy. H&E staining and immunofluorescence staining were used to observe the tumor inhibition markers. RESULTS: T cells and a marked suppression of regulatory T cells compared to the control group. The expression of Ki67 was significantly downregulated, and TUNEL staining revealed an increased number of apoptotic cells in the combination treatment group. Furthermore, the tumor growth rate in the combination treatment group was significantly slower than that in the control group. CONCLUSIONS: E. coli exhibits potential anti-tumor activity and can activate the innate immune response and further regulate immune cells in the tumor tissues to synergize the effect of anti-PD-1 therapy on GBM, providing new insights to enhance the efficacy of GBM immunotherapy.

  PublisherOA PDFDOI

• Staged Low‐Frequency Ultrasound Synergized with Composite Hydrogel to Achieve “Rapid Antimicrobial‐Ordered Regeneration” of Infected Wounds

  Advanced Healthcare Materials · 2025-10-23 · 1 citations

  article

  Bacterial-infectious wounds present a significant threat to global health due to an altered microenvironment that promotes drug-resistant bacterial persistence. Given the limitations of traditional dressings, static drug release mechanisms, and singular antibacterial action, along with the issue of drug resistance exacerbated by the overuse of antibiotics, a dual dynamic cross-linked network composite hydrogel (CSGA-Cip) is developed to overcome these challenges. The hydrogel forms a dynamic adaptive network through Schiff base bonds and Ag─S coordination bonds, endowing it with injectable and self-healing properties. Notably, a staged low-frequency ultrasound intervention strategy is employed to achieve a cascade treatment of antibacterial ordered regeneration. During acute infection (0-3 days), continuous low-frequency ultrasound facilitates the rapid release of silver ions (Ag⁺) and ciprofloxacin (Cip), synergizing with glutathione (GSH) to establish multiple antibacterial barriers. In the repair stage (3-9 days), pulsed low-frequency ultrasound activated cell migration and angiogenesis signaling pathways to guide tissue regeneration. Animal studies have confirmed that this strategy significantly enhances infectious wound healing, promotes orderly collagen deposition, and stimulates angiogenesis, thereby providing an innovative paradigm for the treatment of infectious wounds.

  PublisherDOI

• Discovery of CRBN-recruiting PROTAC degraders of the METTL3-METTL14 complex

  Medicinal Chemistry Research · 2025-09-05 · 3 citations

  articleOpen access

  Abstract METTL3 and METTL14, key components of the m 6 A writer complex, are frequently overexpressed in various malignancies, including acute myeloid leukemia (AML), where aberrant methylation has been linked to the upregulation of oncogenic transcription. Therefore, targeting the METTL3/METTL14 complex represents a potential therapeutic approach for AML. Although several METTL3 inhibitors have been discovered, their SAM-competitive mode of action often results in reduced cellular potency, prompting interest in alternative strategies such as targeted protein degradation. In this article, we expand upon reported METTL3/METTL14 complex degraders through exploration of CRBN-recruiting proteolysis-targeting chimeras (PROTACs) from multiple exit vectors of UZH2, a reported METTL3 inhibitor. The most potent PROTAC, 4j , demonstrated sub-micromolar degradation potency in MV4.11 cells with DC 50 values of 0.44 µM for METTL3 and 0.13 µM for METTL14. Notably, 4j showed enhanced cytotoxicity in MV4.11 cells compared to well-validated METTL3 inhibitors, underscoring the therapeutic potential of targeted degradation of the METTL3/METTL14 complex in AML.

  PublisherOA PDFDOI

• Harnessing Chimeric Degrader Technologies for Antimicrobial Innovation

  Journal of Medicinal Chemistry · 2025-10-14 · 2 citations

  articleSenior authorCorresponding

  Infectious diseases remain a major global health threat, with bacterial and viral pathogens responsible for a majority of cases in both humans and animals. While small-molecule inhibitors have been the cornerstones of antimicrobial therapy, their effectiveness is increasingly undermined by the rapid emergence of drug-resistant strains. Targeted protein and RNA degradation represent a novel therapeutic modality that offers key advantages over conventional inhibition-based strategies, including catalytic activity, improved selectivity, the ability to target previously "undruggable" proteins and RNA structures, and the potential to repurpose shelved or discontinued drugs. Building on the clinical success of degraders in oncology, this perspective explores recent advances in targeted degradation approaches, particularly PROTACs, BacPROTACs, homo-BacPROTACs, AUTACs, RIBOTACs, and PINADs, for bacterial and viral infections. We also discuss future perspectives and key design considerations for translating this emerging modality into clinical anti-infective agents.

  PublisherDOI

• A BCL-xL/BCL-2 PROTAC effectively clears senescent cells in the liver and reduces MASH-driven hepatocellular carcinoma in mice

  Nature Aging · 2025-01-31 · 37 citations

  articleOpen access
  PublisherOA PDFDOI

Recent grants

• Discovery and Target Identification of Senolytic Agents

  NIH · $373k · 2017–2019

• NIH Grant R21DA030667

  NIH · $408k · 2014

• Develop BCL-xL proteolysis targeting chimeras as safer and better senolytics

  NIH · $2.6M · 2019–2025

• Identifying Novel Senolytic Agents and Molecular Targets

  NIH · $378k · 2020–2022

• NCI Clinical and Translational Exploratory/ Developmental Studies

  NIH · $359k · 2018–2020

Frequent coauthors

• Daohong Zhou

  The University of Texas Health Science Center at Houston

  95 shared

• Peter A. Crooks

  University of Arkansas for Medical Sciences

  87 shared

• Linda P. Dwoskin

  University of Kentucky

  82 shared

• Xuan Zhang

  56 shared

• Peiyi Zhang

  44 shared

• Weizhou Zhang

  Suzhou Chien-Shiung Institute of Technology

  43 shared

• Xingui Liu

  University of Dundee

  38 shared

• Chengde Liao

  Kunming Medical University

  37 shared

Labs

• Department of Cellular and Systems PharmacologyPI

Education

• B.S., Medicinal Chemistry

  Fudan University

• Ph.D., Synthetic Organic Chemistry

  Shanghai Institute of Materia Medica

• Other, Drug Design and Discovery

  University of Kentucky College of Pharmacy