Life Sciences Seminar: Development of a potent and selective FGFR4 inhibitor for the treatment of Hepatocellular Carcinoma
Development of a potent and selective FGFR4 inhibitor for the treatment of Hepatocellular Carcinoma
Dr. Renata Rezende Miranda
Postdoctoral Associate
Thomas H. Gosnell School of Life Sciences, RIT
Abnormal activation of the fibroblast growth factor receptor 4 FGFR4 signaling pathway has been shown to drive the proliferation of a significant portion of Hepatocellular Carcinoma, which is a type of primary liver cancer. Dr. Miranda will report the development and biological characterization of a covalent inhibitor that is highly potent and specific to FGFR4.
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.
Speaker Bio:
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 (2021). At USC, her research focused primarily on the development of covalent inhibitors to probe biology and identify new lead compounds for anticancer therapeutic intervention. In Fall 2021, Renata joined the Thomas H. Gosnell School of Life Sciences at the Rochester Institute of Technology as a Postdoctoral Associate in Dr. Hudson’s Lab. Renata’s current research interests have shifted to the world of microbiology, and her work with Dr. Hudson will be directed towards the discovery and characterization of novel antibiotic lead compounds.
Intended Audience:
Beginners, undergraduates, graduates. Those with interest in the topic.
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