title: Discovery of Bifunctional Oncogenic Target Inhibitors against Allosteric Mitogen-Activated Protein Kinase (MEK1) and Phosphatidylinositol 3-Kinase (PI3K).
abstract: The synthesis of a series of single entity, bifunctional MEK1/PI3K inhibitors achieved by covalent linking of structural analogs of the ATP-competitive PI3K inhibitor ZSTK474 and the ATP-noncompetitive MEK inhibitor PD0325901 is described. Inhibitors displayed potent in vitro inhibition of MEK1 (0.015 < IC50 (nM) < 56.7) and PI3K (54 < IC50 (nM) < 341) in enzymatic inhibition assays. Concurrent MEK1 and PI3K inhibition was demonstrated with inhibitors 9 and 14 in two tumor cell lines (A549, D54). Inhibitors produced dose-dependent decreased cell viability similar to the combined administration of equivalent doses of ZSTK474 and PD0325901. In vivo efficacy of 14 following oral administration was demonstrated in D54 glioma and A549 lung tumor bearing mice. Compound 14 showed a 95% and 67% inhibition of tumor ERK1/2 and Akt phosphorylation, respectively, at 2 h postadministration by Western blot analysis, confirming the bioavailability and efficacy of this bifunctional inhibitor strategy toward combined MEK1/PI3K inhibition.
authors.affiliation: Center for Molecular Imaging, ‡Department of Radiology, and §Department of Biological Chemistry, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Marcian E
authors.initials: ME
authors.lastname: Van Dort
authors.affiliation: Center for Molecular Imaging, ‡Department of Radiology, and §Department of Biological Chemistry, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Hao
authors.initials: H
authors.lastname: Hong
authors.affiliation: Center for Molecular Imaging, ‡Department of Radiology, and §Department of Biological Chemistry, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Hanxiao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Center for Molecular Imaging, ‡Department of Radiology, and §Department of Biological Chemistry, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Nino
authors.affiliation: Center for Molecular Imaging, ‡Department of Radiology, and §Department of Biological Chemistry, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Lombardi
authors.affiliation: Center for Molecular Imaging, ‡Department of Radiology, and §Department of Biological Chemistry, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Avery E
authors.initials: AE
authors.lastname: Blanks
authors.affiliation: Center for Molecular Imaging, ‡Department of Radiology, and §Department of Biological Chemistry, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Galbán
authors.affiliation: Center for Molecular Imaging, ‡Department of Radiology, and §Department of Biological Chemistry, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Ross
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D055808:Drug Discovery; D005260:Female; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C506614:mirdametinib; D004159:Diphenylamine; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human