title: Biophysical characterization of drug-resistant mutants of fibroblast growth factor receptor 1.
abstract: Over-expression and aberrant activation of tyrosine kinases occur frequently in human cancers. Various tyrosine kinase inhibitors (TKIs) are under clinical use, but acquisition of resistance to these drugs is a major problem. Here, we studied the interaction between two drug-resistant mutants of fibroblast growth factor receptor 1 (FGFR1), N546K and V561M, and four ATP-competitive inhibitors, ponatinib, dovitinib, PD173074 and BGJ-398. Among these protein-drug systems, the only marked reduction in affinity was that of PD173074 for the V561M mutant. We also examined the interaction of these FGFR1 variants to AMP-PNP, a nonhydrolyzable analogue of ATP, and showed that N546K showed increased affinity for the ATP analogue as compared with the wild type. These findings will help to clarify the mechanism of drug resistance in mutant tyrosine kinases.
authors: Department of Analytical and Biophysical Chemistry, School of Pharmacy, Kumamoto University, Kumamoto, 862-0973, Japan.
authors: Kaito
authors: K
authors: Yoza
authors: Department of Analytical and Biophysical Chemistry, School of Pharmacy, Kumamoto University, Kumamoto, 862-0973, Japan.
authors: Rika
authors: R
authors: Himeno
authors: Department of Structural Biology, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Hokkaido, 060-0810, Japan.
authors: Shinjiro
authors: S
authors: Amano
authors: Department of Analytical and Biophysical Chemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan. kob@kumamoto-u.ac.jp.
authors: Yoshihiro
authors: Y
authors: Kobashigawa
authors: Department of Analytical and Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, 862-0973, Japan.
authors: Shun
authors: S
authors: Amemiya
authors: Department of Analytical and Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, 862-0973, Japan.
authors: Natsuki
authors: N
authors: Fukuda
authors: Department of Structural Biology, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Hokkaido, 060-0810, Japan.
authors: Hiroyuki
authors: H
authors: Kumeta
authors: Department of Analytical and Biophysical Chemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan.
authors: Hiroshi
authors: H
authors: Morioka
authors: Department of Structural Biology, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Hokkaido, 060-0810, Japan.
authors: Fuyuhiko
authors: F
authors: Inagaki
mesh_terms: D000266:Adenylyl Imidodiphosphate / Q000378:metabolism; D001562:Benzimidazoles / Q000378:metabolism / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics; D005470:Fluorometry; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000378:metabolism / Q000494:pharmacology; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology; D015363:Quinolones / Q000378:metabolism / Q000494:pharmacology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D013050:Spectrometry, Fluorescence
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D001562:Benzimidazoles; D007093:Imidazoles; C115711:PD 173074; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011743:Pyrimidines; D015363:Quinolones; D000266:Adenylyl Imidodiphosphate; C545373:ponatinib; D051496:Receptor, Fibroblast Growth Factor, Type 1