title: Aurora kinase A is a possible target of OSU‑03012 to destabilize MYC family proteins.
abstract: OSU-03012, a 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitor, destabilizes MYCN and MYC proteins in neuroblastoma cells. However, AKT phosphorylation is barely detectable in neuroblastoma cells under normal culture conditions whether treated with OSU-03012 or not. This observation suggests that PDK1 is not the main target of OSU-03012 to destabilize MYC and MYCN in neuroblastoma cells. In the present study, we explored one of the possible mechanisms by which OSU-03012 destabilizes MYC and MYCN. Since Aurora kinase A is reported to phosphorylate GSK3β, leading to its inactivation, we hypothesized that one of the targets of OSU-03012 is Aurora kinase A. Comparative analysis of OSU-03012 and VX-680, a potent and specific inhibitor of Aurora kinases, showed that both inhibitors destabilized MYC and MYCN and were significantly growth suppressive to neuroblastoma cell lines. In silico molecular docking analysis further showed that the calculated interaction energy between Aurora kinase A and OSU-03012 was -109.901 kcal/mol, which was lower than that (-89.273 kcal/mol) between Aurora kinase A and FXG, an Aurora kinase-specific inhibitor. Finally, an in vitro Aurora kinase A inhibition assay using a recombinant Aurora kinase A showed that OSU-03012 significantly inhibited Aurora kinase A, although it was weaker in potency than that of VX-680. Thus, OSU-03012 has a likelihood of binding to and inhibiting Aurora kinase A in vivo. These results suggest that OSU-03012 affects multiple cellular targets, including Aurora kinase A, to exhibit its growth suppressive and MYC and MYCN-destabilizing effects on neuroblastoma and other cancer cells.
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Silva
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Jennie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Lomahan
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Tuan-Anh
authors.initials: TA
authors.lastname: Tran
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Grenlin
authors.affiliation: Department of Bioinformatics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Suganami
authors.affiliation: Department of Bioinformatics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tamura
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Naohiko
authors.initials: N
authors.lastname: Ikegaki
mesh_terms: D064096:Aurora Kinase A / Q000737:chemistry / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D062105:Molecular Docking Simulation; D009447:Neuroblastoma / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D003521:Cyclopropanes; D011743:Pyrimidines
chemical_list: D064096:Aurora Kinase A; D010879:Piperazines; D016271:Proto-Oncogene Proteins c-myc; D011720:Pyrazoles; D013449:Sulfonamides; C500894:OSU 03012; C484810:tozasertib; D003521:Cyclopropanes; D011743:Pyrimidines; C576917:AURKA protein, human