Advisor(s) - Committee Chair
Dr. Rajalingam Dakshinamurthy (Director), Dr. Rui Zhang, Dr. Cathleen Webb
Department of Chemistry
Master of Science
Fibroblast growth factors (FGFs) lack signal sequences, and are exported through endoplasmic reticulum (ER)-Golgi-independent non-classical routes. FGFs work as modulators of various cellular activities like mitosis, differentiation, survival etc. Among the FGF family, which comprises of 23 different heparin proteins, human FGF-1 (hFGF-1), a potent angiogenic factors are one of the targets in cancer inhibition, as they are involved in blood vessel formation in tissues. There has been intensive research directed at the development of drugs that could effectively inhibit angiogenesis. In this context, the purpose of this study is to fully understand the molecular principles essential to determine probability of inhibition of hFGF-1 signaling transduction by imatinib. Imatinib, a 2-phenyl amino pyrimidine derivative is a tyrosine kinase inhibitor with antineoplastic activity. Imatinib binds to the intracellular pocket located within tyrosine kinases and inhibit the downstream cell proliferation events, but the exact molecular mechanism is still elusive. In this study, expression of hFGF-1 in recombinant E. coli was carried out, and the expressed protein was purified using heparin affinity column chromatography. The structural interactions governing imatinib-hFGF-1 interaction was studied by monitoring its stability, conformation and binding affinity by equilibrium unfolding using steady state fluorescence and proteolytic digestion assay. These data show that imatinib binds to hFGF-1 and enhances its thermal stability and solvent accessibility. In addition, biacore analysis was carried out to determine the binding affinity of imatinib to hFGF-1.
Biochemistry, Biophysics, and Structural Biology | Chemistry
Modi, Tulsi, "Understanding the Molecular Level Interactions of Cancer Inhibitor Imatinib with Human Fibroblast Growth Factor-1" (2015). Masters Theses & Specialist Projects. Paper 1492.
Available for download on Thursday, May 10, 2018