The Zheng laboratory focuses on design, synthesis, and structure-activity relationship studies of synthetically derived and natural product-based compounds for therapeutic use or as molecular probes for further biochemical and pharmacological research.
Based at the University of Florida (UF), our research program involves an interdisciplinary approach centered on drug discovery and development. We collaborate extensively with experts in cancer biology, immunology, cellular senescence, and neuroscience, using novel approaches in medicinal chemistry to develop novel drug candidates for various human diseases, including cancer and age-related diseases. A major focus for our lab is the design and development of bivalent small-molecules capable of modulating protein-protein interactions, including those that induce targeted protein degradation.
Our lab is currently actively pursuing three main areas of drug discovery:
- Drug discovery based on the proteolysis-targeting chimera (PROTAC) technology
- Discovery and target identification of senolytics
- Targeting tumor immunosuppressives in the tumor microenvironment
Drug discovery based on the proteolysis-targeting chimera (PROTAC) technology
PROTACs are bivalent molecules containing a pharmacophoric unit that recognizes the target protein linked to a second pharmacophoric unit that binds to a specific E3 ubiquitin ligase complex. They recruit the target protein to the E3 ligase complex, promote proximity-induced poly-ubiquitination of the target protein, and lead to target protein degradation by proteasomes (Figure 1). Since 2015, our group has been focused on building a drug discovery platform based on the PROTAC targeted protein degradation technology. We aim to develop compounds that have the potential for therapeutic translation or as tool molecules for chemical biology studies.
We collaborate extensively with Dr. Daohong Zhou’s group as well as with researchers at the UF Health Cancer Center (UFHCC) and others around the county to explore many potential applications of this emerging technology. Our most advanced project is the development of PROTACs targeting Bcl-xL for degradation. Bcl-xL is a high value and well-validated cancer target; however, inhibition of Bcl-xL causes severe thrombocytopenia because platelets depend on Bcl-xL to maintain their viability. We have coupled the PROTAC technology with an innovative concept of E3 ligase-based tissue specific induction of target protein degradation to overcome the dose-limiting thrombocytopenia associated with Bcl-xL inhibition because platelets express low levels of E3 ligases (Figure 2). This approach has led to a breakthrough in this field (AACR; Biocentury; Worldpharmanews). Importantly, we have identified DT2216 as a potential first-in-class Bcl-xL degrader for cancer treatments. DT2216 is currently in Phase 1 clinical trial (NCT04886622).
We have built and continue to expand a library of linker and E3 ubiquitin ligase ligand precursors so that PROTACs can be quickly assembled once a protein target of interest and the corresponding ligands are identified. We are also working on expanding the toolbox of the PROTAC technology by discovering novel E3 ligases and novel E3 ligase ligands. An ultimate goal is to develop cell/tissue specific PROTACs based on E3 ligases that are expressed in high levels in cancer cells or senescent cells.
Discovery and target identification of senolytics
Advancing age is the greatest risk factor for the development of many debilitating diseases and conditions. The majority of current drug discovery and development efforts on age-related diseases focuses on tackling each of these diseases separately, with little consideration of the context of aging. We aim to develop pharmacological interventions that target the causes of aging, thus tackling the root cause of age-related diseases. Cellular senescence has emerged as a potential therapeutic target for aging and a broad range of age-related diseases. In collaboration with Dr. Zhou, we are pioneering in the field of discovery and development of senolytics, referring to small molecules that can selectively kill senescent cells. Several novel senolytics and senolytic targets have been identified in our laboratories (Aging 2016 & 2019; Aging Cell 2018 & 2020; Nat Commun 2020). In addition to structural modifications and SAR studies, we also use chemical proteomics approaches to identify novel proteins that are important for senescent cell survival thus can be used as targets for the development of novel senolytic agents.
Targeting tumor immunosuppressives in the tumor microenvironment
We have recently started to build collaborations with several researchers at UFHCC to explore various ways to target tumor immunosuppressive mechanisms in the tumor microenvironment. For example, we have been collaborating with Drs. Weizhou Zhang to develop compounds that specifically target tumor-infiltrating regulatory T cell (TI-Treg) and activate immunity. This collaboration has resulted in one publication (Nat Commun 2021) and three funded grants.