title: N-(2,4)-dinitrophenyl-L-arginine Interacts with EphB4 and Functions as an EphB4 Kinase Modulator.
abstract: The erythropoietin-producing hepatocellular carcinoma receptor B4 is a receptor tyrosine kinase whose expression is preserved in various malignancies, including colon, gastric, and breast carcinoma. Hepatocellular carcinoma receptor B4 presence in tumor cells and involvement in cancer suppression makes it a potential therapeutic target for activating compounds. Moreover, modulators of its activity also have a strong potential to be used in diagnosis and therapy monitoring. We used virtual ligand screening to identify novel hepatocellular carcinoma receptor B4 kinase modulators for experimental testing. Three independent assay platforms confirmed that dinitrophenyl-L-arginine is likely to affect the kinase activity of hepatocellular carcinoma receptor B4. An enzyme-coupled spectrophotometric assay has been used to examine this possibility and may prove to be useful for assessing other novel kinase modulator candidates. Overall, our observations suggest that dinitrophenyl-L-arginine has an activating effect on hepatocellular carcinoma receptor B4 and, therefore, more efficient derivatives may have therapeutic effects in tumors where hepatocellular carcinoma receptor B4 exhibits antimalignant properties. The hepatocellular carcinoma receptor B4-activating effect is discussed with respect to previously described mechanisms, using predicted and experimental structures for docked ligands. As a novel kinase activity modulator, dinitrophenyl-L-arginine may provide new insights into molecular mechanisms by which kinases are activated or regulated, and may serve as a lead compound for the generation of novel hepatocellular carcinoma receptor B4-activating therapeutic compounds.
authors.affiliation: Department of Chemistry, Lakehead University, Thunder Bay, ON, P7B 5E1, Canada.|Thunder Bay Regional Research Institute, Thunder Bay, ON, P7A 7T1, Canada.
authors.forename: Rhiannon L
authors.initials: RL
authors.lastname: Kamstra
authors.affiliation: Department of Pathology, University of Saskatchewan, Saskatoon, SK, S7N 0W0, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Freywald
authors.affiliation: Department of Chemistry, Lakehead University, Thunder Bay, ON, P7B 5E1, Canada.|Thunder Bay Regional Research Institute, Thunder Bay, ON, P7A 7T1, Canada.
authors.forename: Wely B
authors.initials: WB
authors.lastname: Floriano
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D001120:Arginine / Q000031:analogs & derivatives* / Q000737:chemistry*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology; D004136:Dinitrobenzenes / Q000737:chemistry*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000378:metabolism; D036224:Receptor, EphB4 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004136:Dinitrobenzenes; D009363:Neoplasm Proteins; D001120:Arginine; D036224:Receptor, EphB4
keywords: Eph kinase; HierVLS; hepatocellular carcinoma receptor B4; receptor tyrosine kinase modulator; virtual ligand screening