John V. O'Connor Assistant Professor of Cancer Drug Discovery
Department of Chemistry and Biochemistry
The classic paradigm that only folded protein structure leads to function has been rewritten to recognize the significant role dynamic and/or disordered regions play in biology. These structures are central to protein ensembles and allosteric networks, signaling hubs and cellular machines, and the formation and dissolution of biomolecular condensates. Dynamic and disordered proteins have also been implicated as drivers of numerous diseases and thus are promising therapeutic targets. These structures, however, are largely considered unligandable and consequently undruggable.
The Morgan lab uses covalent small molecules to capture dynamic and/or disordered protein structures and study their molecular recognition. Through our approach, we answer many broad and fundamental questions: Can dynamic and/or disordered regions be targeted specifically and selectively with small molecules? What are the molecular interactions that form between the ligand and protein? How does the ligand alter the structure and conformational landscape of the protein? Does small molecule binding to these regions alter protein activity?
To answer these questions, our lab uses RNA-binding proteins (RBPs) as a model system. RBPs are enriched with dynamic and disordered regions, are genetically mutated in over 200 diseases, and have largely eluded selective small molecule targeting. Our initial focus is on i) developing covalent ligand discovery strategies tailored to dynamic loops and intrinsically disordered regions; ii) utilizing discovered probes to explore RBP structure and function; and iii) explore the therapeutic potential of RBPs in cancer proliferation and metastasis.
Research in the Morgan lab is highly interdisciplinary. We utilize computational methods to design covalent libraries, medicinal chemistry to optimize ligands into preclinical drug candidates, and biochemical, structural, biophysical, and cell culture techniques to characterize the effects of ligands on RBP structure and function.
- Matthew J. Henley, Brian M. Linhares, Brittany S. Morgan, Tomasz Cierpicki, Carol A. Fierke, and Anna K. Mapp. “Unexpected Specificity within Dynamic Transcriptional Protein-Protein Complexes.” Proc. Natl. Acad. Sci. U. S. A. 2020, DOI: 10.1073/pnas.2013244117.
- Anita Donlic, Brittany S. Morgan, Jason L. Xu, Anqi Liu, Carlos Roble Jr., and Amanda E. Hargrove. “Discovery of Small Molecule Ligands for MALAT1 by Tuning an RNA-Binding Scaffold,” Angew. Chem., Int. Ed. Engl. 2018, 57 (40), 13242.
- Brittany S. Morgan, Jordan E. Forte, Rebecca N. Culver, Yuqi Zhang, and Amanda E. Hargrove. “Discovery of Key Physicochemical, Structural, and Spatial Properties of RNA-Targeted Bioactive Ligands,” Angew. Chem., Int. Ed. Engl. 2017, 56 (43), 13498.