Zhengyu Wang

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.