Neurosurgery Research Seminar – David E. Heppner, PhD
January 29 @ 3:00 pm - 4:00 pm
Thursday, January 29, 2026, 3:00 p.m. in MSB 2.135
David E. Heppner, PhD
J. Solo Assistant Professor of Medicinal Chemistry, Department of Chemistry, The State University of New York at Buffalo
Associate Editor, Journal of Medicinal Chemistry
Title of talk: Structure-forward Studies of EGFR Inhibitors and Their Impact on Drug Discovery
Targeted therapies against activating mutations in the epidermal growth factor receptor (EGFR) have become well-established cancer treatments. Successive generations of inhibitors have evolved in response to drug-resistant mutations producing a diverse arsenal of compounds, encompassing both reversible non-covalent and irreversible covalent mechanisms. A central driver of this progress has been the extensive use of structural biology, specifically X-ray crystallography, to elucidate inhibitor binding modes within the kinase active site, thereby guiding structure-based design. To further explore the molecular basis by which EGFR inhibitors achieve their critical pharmacological properties, we employed a structure-forward approach to prioritize studies of compounds through structurally enabled methods. We have determined the structural basis of third-generation irreversible covalent inhibitors and applied kinetic assays to deepen our understanding of covalent inhibitor profiling—an approach broadly relevant to all covalent inhibitor campaigns. Additionally, we developed ATP-allosteric bivalent inhibitors (AABIs), establishing a foundation for new directions in kinase inhibitor development. Uniquely, these studies are uncovering previously unrecognized strategies for optimizing the structures of adjoined compounds especially relevant to fragment-based drug discovery. Through the generation of structural and mechanistic insights, our work highlights the EGFR drug target as an effective model system for assessing the status quo in drug discovery and driving innovation that contribute to improving the pace and efficiency in medicinal chemistry.