title: Evaluating p97 Inhibitor Analogues for Potency against p97-p37 and p97-Npl4-Ufd1 Complexes.
abstract: We previously found that the p97 cofactor, p47, significantly decreased the potency of some ATP-competitive p97 inhibitors such as ML240 [2-(2-amino-1H-benzo[d]imidazol-1-yl)-N-benzyl-8-methoxyquinazolin-4-amine] and ML241 [2-(2H-benzo[b][1,4]oxazin-4(3H)-yl)-N-benzyl-5,6,7,8 tetrahydroquinazolin-4-amine]. In this study, we aimed to evaluate inhibitor potencies against two additional p97 cofactor complexes, p97-p37 and p97-Npl4-Ufd1. We focused on these two cofactor complexes, because the protein sequence of p37 is 50 % identical to that of p47, and the Npl4-Ufd1 heterodimer (NU) is the most-studied p97 cofactor complex. We screened 200 p97 inhibitor analogues for their ability to inhibit the ATPase activity of p97 alone and of p97-p37 and p97-NU complexes. In contrast to the effect of p47, p37 and NU did not significantly change the potencies of most of the compounds. These results highlight differences among p97 cofactors in influencing p97 conformation and effects of inhibitors on p97 complexes, as compared to p97 alone. Continued efforts are needed to advance the development of complex-specific p97 inhibitors.
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, 1124 W. Carson St, Torrance, CA, 90502, USA.|School of Chemical Biology and Pharmaceutical Sciences, Capital Medical University, Beijing, 100069, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: Gui
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, 1124 W. Carson St, Torrance, CA, 90502, USA.|School of Chemical Biology and Pharmaceutical Sciences, Capital Medical University, Beijing, 100069, PR China.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Specialized Chemistry Center, University of Kansas, 2034 Becker Drive, Lawrence, KS, 66047-3761, USA.
authors.forename: Kelin
authors.initials: K
authors.lastname: Li
authors.affiliation: Specialized Chemistry Center, University of Kansas, 2034 Becker Drive, Lawrence, KS, 66047-3761, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Frankowski
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, 1124 W. Carson St, Torrance, CA, 90502, USA.|School of Chemical Biology and Pharmaceutical Sciences, Capital Medical University, Beijing, 100069, PR China.
authors.forename: Shan
authors.initials: S
authors.lastname: Li
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, 1124 W. Carson St, Torrance, CA, 90502, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Wong
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, 1124 W. Carson St, Torrance, CA, 90502, USA.
authors.forename: Derek R
authors.initials: DR
authors.lastname: Moen
authors.affiliation: Specialized Chemistry Center, University of Kansas, 2034 Becker Drive, Lawrence, KS, 66047-3761, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Porubsky
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, 1124 W. Carson St, Torrance, CA, 90502, USA.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Lin
authors.affiliation: Specialized Chemistry Center, University of Kansas, 2034 Becker Drive, Lawrence, KS, 66047-3761, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Schoenen
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, 1124 W. Carson St, Torrance, CA, 90502, USA. tsuifenchou@ucla.edu.
authors.forename: Tsui-Fen
authors.identifier: 0000-0003-2410-2186
authors.initials: TF
authors.lastname: Chou
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D000074405:Valosin Containing Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; C514112:NPLOC4 protein, human; D009687:Nuclear Proteins; D011506:Proteins; C491497:UFD1 protein, human; C553975:p37 protein, human; D000251:Adenosine Triphosphatases; D000074405:Valosin Containing Protein
keywords: ATPase; cancer; p97; structure-activity relationships; ubiquitin-proteasome system