Discovery of (7-aryl-1,5-naphthyridin-2-yl)ureas as dual inhibitors of ERK2 and Aurora B kinases with antiproliferative activity against cancer cells

Julien Defaux; Maud Antoine; Cédric Logé; Marc Le Borgne; Tilmann Schuster; Irene Seipelt; Babette Aicher; Michael Teifel; Eckhard Günther; Matthias Gerlach; Pascal Marchand

doi:10.1016/j.bmcl.2014.06.078

Discovery of (7-aryl-1,5-naphthyridin-2-yl)ureas as dual inhibitors of ERK2 and Aurora B kinases with antiproliferative activity against cancer cells

Bioorg Med Chem Lett. 2014 Aug 15;24(16):3748-52. doi: 10.1016/j.bmcl.2014.06.078. Epub 2014 Jul 3.

Affiliations

¹ Université de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, Cibles et Médicaments des Infections et du Cancer IICiMed EA 1155, UFR des Sciences Pharmaceutiques et Biologiques, 1 rue Gaston Veil, 44035 Nantes, France.
² Æterna Zentaris GmbH, Weismuellerstrasse 50, 60314 Frankfurt/Main, Germany.
³ Université de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, Cibles et Médicaments des Infections et du Cancer IICiMed EA 1155, UFR des Sciences Pharmaceutiques et Biologiques, 1 rue Gaston Veil, 44035 Nantes, France. Electronic address: pascal.marchand@univ-nantes.fr.

PMID: 25022204
DOI: 10.1016/j.bmcl.2014.06.078

Abstract

A novel series of (7-aryl-1,5-naphthyridin-2-yl)ureas was discovered as dual ERK2 and Aurora B kinases inhibitors. Several analogues were active at micromolar and submicromolar range against ERK2 and Aurora B, associated with very promising antiproliferative activity toward various cancer cell lines. Synthesis, structure activity relationship and docking study are reported. In vitro ADME properties and safety data are also discussed.

Keywords: 1,5-Naphthyridine; Antitumor activity; Aurora B; ERK2; Kinase inhibitor.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Aurora Kinase B / antagonists & inhibitors*
Aurora Kinase B / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
HCT116 Cells
Humans
Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
Mitogen-Activated Protein Kinase 1 / metabolism
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Urea / analogs & derivatives
Urea / chemistry
Urea / pharmacology*

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Urea
Aurora Kinase B
Mitogen-Activated Protein Kinase 1