Biomedical and Chemical Engineering Research Seminar Series - Development of covalent small molecules as targeted therapies and chemical probes

Title: Development of covalent small molecules as targeted therapies and chemical probes 

Abstract: Abnormal activation of the fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) signaling pathway has been shown to drive the proliferation of a significant portion of Hepatocellular Carcinoma (HCC), which is a type of primary liver cancer. Resistance and toxicity are serious drawbacks that have been observed upon use of the current first- and second-line treatment options for HCC, therefore warranting the investigation of alternative therapeutic approaches. We report the development and biological characterization of a covalent inhibitor that is highly potent and specific to FGFR4. The crystal structure of this inhibitor in complex with FGFR4 was solved, confirming its covalent interaction with a rare cysteine residue and its binding mode to the protein’s active site. We also describe the first clickable probe for FGFR4 that can be used to directly measure target engagement of this protein kinase in cells. Our compound exhibited great anti-tumor activity in HCC cell lines and tumor xenograft models. These results provide evidence of a promising therapeutic lead for the treatment of a subset of HCC patients. 

Short bio: Dr. Renata Rezende Miranda is a chemist with expertise in organic synthesis of small molecules, medicinal chemistry, and chemical biology. She earned her Ph.D. degree in Chemistry from the University of Southern California in July 2021. At USC, her research focused primarily on the development of selective covalent kinase inhibitors as new lead compounds for anticancer therapy. In Fall 2021, Dr. Miranda joined the Thomas H. Gosnell School of Life Sciences at the Rochester Institute of Technology as a Postdoctoral Associate working with Dr. André Hudson on projects involving the discovery and characterization of novel antibiotic lead compounds from bacteria. In Fall 2023, she started a new position as Assistant Professor in RIT’s School of Chemistry and Materials Science. Her current research focuses on the development of chemical probes to study diverse biological processes in bacteria and advance antibiotic drug discovery.