2. Academic Validation
  3. Towards the development of chromone-based MEK1/2 modulators

Towards the development of chromone-based MEK1/2 modulators

  • Eur J Med Chem. 2014 Oct 6:85:127-38. doi: 10.1016/j.ejmech.2014.07.018.
Itedale Namro Redwan 1,  Christine Dyrager 1,  Carlos Solano 1,  Guillermo Fernández de Trocóniz 1,  Laure Voisin 2,  David Bliman 1,  Sylvain Meloche 2,  Morten Grøtli 3
Affiliations

Affiliations

  • 1 Department of Chemistry and Molecular Biology, Medicinal Chemistry, University of Gothenburg, SE-41296 Göteborg, Sweden.
  • 2 Institute of Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec H3C 3J7, Canada.
  • 3 Department of Chemistry and Molecular Biology, Medicinal Chemistry, University of Gothenburg, SE-41296 Göteborg, Sweden. Electronic address: grotli@chem.gu.se.
PMID: 25078316 DOI: 10.1016/j.ejmech.2014.07.018
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.

Keywords

Antiproliferative activity; Biochemical activity; Chromones; Kinase selectivity profile; Mitogen-activated protein kinase kinases; Molecular modeling; Whole-cell assay.

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