Heather Murrey, PhD, Senior Director of Chemical Biology at Scorpion Therapeutics

Recent chemoproteomics advances have enabled covalent ligand discovery across a broad range of oncology targets.  Here, Dr. Murrey will discuss the expanding role of chemical biology and chemoproteomics to support covalent lead discovery efforts, from early hit-finding to late lead optimization.  Dr. Murrey will highlight our development of covalent ligands targeting the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases.  EGFR mutations are key molecular drivers that underlie a subset of non-small cell lung cancer (NSCLC) tumors.  These mutations include EGFR Exon 20 insertion mutations, which represent about 3-5% of all NSCLC tumors.  Despite the prevalence of these mutations, development of targeted therapies with selectivity over wild-type EGFR remain elusive.  Here, we characterize EGFR inhibitor activity, including the recently-FDA approved therapeutic Mobocertinib, towards both wild-type and exon 20 insertion mutant EGFR using a covalent, activity-based probe targeting C797 in the EGFR active site.  Using this probe, we developed a single, high-throughput alphaLISA assay to investigate EGFR inhibitor mutant/wild-type selectivity, in vivo EGFR target occupancy, and identified a series of covalent compounds targeting an alternative cysteine residue within the EGFR active site.

BIO

Heather E. Murrey, Ph.D. is currently a Senior Director in the Chemical Biology and Chemoproteomics group at Scorpion Therapeutics, a precision oncology company founded in February 2020 by a preeminent group of scientists from Harvard University/Massachusetts General Hospital.  Here, she serves as a program lead and directs program support across the company portfolio.  Prior to joining Scorpion, Heather worked at Janssen, where she supported covalent inhibitor development using novel chemical biology and chemoproteomics assays.  Heather holds a joint B.A./M.S. in Biochemistry from Brandeis University, trained with Peter Kim and Harvey Lodish at the (Whitehead Institute, MIT) and completed her Ph.D. in Biochemistry and Molecular Biophysics at the California Institute of Technology working with Professor Linda Hsieh-Wilson, where her work focused on exploring bioorthogonal tool compounds to characterize neuronal glycans involved in neuronal signaling.  She was a postdoctoral fellow at the Scripps Research Institute with Professor Benjamin Cravatt followed by Pfizer (Cambridge, MA) where her work enabled characterization of inhibitor mechanism-of-action.