title: Towards the development of chromone-based MEK1/2 modulators.
abstract: Inhibition or allosteric modulation of mitogen-activated protein kinase kinases MEK1 and MEK2 (MEK1/2) represent a promising strategy for the discovery of new specific anticancer agents. In this paper, structure-based design, beginning from the lead compound PD98059, was used to study potential structural modifications on the chromone structure in order to obtain highly potent derivatives that target the allosteric pocket in MEK1. Subsequently, a small series of PD98059 analogs were synthesized to provide a first generation of chromone-based derivatives that inhibit the activation of MEK1 with IC50 values as low as 30 nM in vitro. Complementary cellular studies also showed that two of the compounds in the series inhibit the activity of MEK1/2 with IC50 values in the nanomolar range (73-97 nM). In addition, compounds in this series were found to inhibit the proliferation of a small panel of human cancer cell lines.
authors: Department of Chemistry and Molecular Biology, Medicinal Chemistry, University of Gothenburg, SE-41296 Göteborg, Sweden.
authors: Itedale Namro
authors: IN
authors: Redwan
authors: Department of Chemistry and Molecular Biology, Medicinal Chemistry, University of Gothenburg, SE-41296 Göteborg, Sweden.
authors: Christine
authors: C
authors: Dyrager
authors: Department of Chemistry and Molecular Biology, Medicinal Chemistry, University of Gothenburg, SE-41296 Göteborg, Sweden.
authors: Carlos
authors: C
authors: Solano
authors: Department of Chemistry and Molecular Biology, Medicinal Chemistry, University of Gothenburg, SE-41296 Göteborg, Sweden.
authors: Guillermo
authors: G
authors: Fernández de Trocóniz
authors: Institute of Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec H3C 3J7, Canada.
authors: Laure
authors: L
authors: Voisin
authors: Department of Chemistry and Molecular Biology, Medicinal Chemistry, University of Gothenburg, SE-41296 Göteborg, Sweden.
authors: David
authors: D
authors: Bliman
authors: Institute of Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec H3C 3J7, Canada.
authors: Sylvain
authors: S
authors: Meloche
authors: Department of Chemistry and Molecular Biology, Medicinal Chemistry, University of Gothenburg, SE-41296 Göteborg, Sweden. Electronic address: grotli@chem.gu.se.
authors: Morten
authors: M
authors: Grøtli
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000737:chemistry*; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000737:chemistry / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000737:chemistry / Q000378:metabolism*; D062105:Molecular Docking Simulation
chemical_list: D000970:Antineoplastic Agents; D002867:Chromones; D005419:Flavonoids; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: Antiproliferative activity; Biochemical activity; Chromones; Kinase selectivity profile; Mitogen-activated protein kinase kinases; Molecular modeling; Whole-cell assay