Research

Our research program is focused on the development of innovative chemical strategies to address challenging problems in medicine and biology. We operate at the interface of organic synthesis, medicinal chemistry, and chemical biology to design and create molecules with therapeutic potential. Our primary research interests are divided into three main areas.

Drug Discovery

Covalent Drug Discovery

Covalent inhibitors have re-emerged as a powerful therapeutic modality, capable of targeting proteins previously considered "undruggable". Our group is focused on the design and synthesis of novel electrophiles for covalent inhibitors. We are particularly interested in leveraging strain-release transformations of highly strained ring systems, such as bicyclo[1.1.0]butanes, to generate unique and highly reactive acrylamide-type warheads. By fine-tuning the electronic and steric properties of these warheads, we aim to achieve high target specificity and potency, while minimizing off-target toxicity.

 Protein-Protein Interaction Inhibitors

Protein-protein interactions (PPIs) represent a vast and largely untapped class of therapeutic targets. However, the typically large and flat interfaces involved in PPIs make them notoriously difficult to target with small molecules. Our laboratory is developing novel strategies to tackle this challenge, with a particular focus on the Nrf2 pathway, a master regulator of the cellular antioxidant response that is frequently dysregulated in cancer. By designing and synthesizing molecules that can selectively modulate this PPI, we aim to restore normal cellular function and sensitize cancer cells to conventional therapies.

Transition-Metal Catalyzed Transformations

Strain-Release Driven Transformations of Bicyclo[1.1.0]butanes

The unique reactivity of bicyclo[1.1.0]butanes (BCBs), driven by their high ring strain, provides a powerful platform for the rapid construction of complex molecular architectures. Our group is exploring the use of transition-metal catalysis, particularly with rhodium(I) complexes, to control the cycloisomerization of BCBs. This strategy allows for the regioselective formation of unprecedented bridged and fused heterocyclic scaffolds from readily available starting materials. We are actively investigating the mechanism of these transformations through computational methods to gain a deeper understanding of the underlying principles and expand the scope of this powerful synthetic methodology.

 C-H Functionalization

Direct C-H functionalization has revolutionized the field of organic synthesis, providing a more efficient and atom-economical approach to the construction of complex molecules. Our laboratory is applying C-H functionalization strategies to synthesize important building blocks for pharmaceutical applications.

 AI for Covalent Drug Design

As the complexity of our molecular designs increases, we are increasingly turning to computational and artificial intelligence (AI) tools to guide our synthetic efforts and accelerate the drug discovery process. We are actively exploring the use of machine learning algorithms to predict the reactivity and selectivity of covalent drugs, and to identify promising new scaffolds for inhibitor development.