Structure-based design of novel quinoxaline-2-carboxylic acids and analogues as Pim-1 inhibitors

  • Eur J Med Chem. 2018 Jun 25:154:101-109. doi: 10.1016/j.ejmech.2018.04.056.
Bruno Oyallon  1 ,  Marie Brachet-Botineau  2 ,  Cédric Logé  3 ,  Pascal Bonnet  4 ,  Mohamed Souab  5 ,  Thomas Robert  5 ,  Sandrine Ruchaud  5 ,  Stéphane Bach  5 ,  Pascal Berthelot  6 ,  Fabrice Gouilleux  7 ,  Marie-Claude Viaud-Massuard  1 ,  Caroline Denevault-Sabourin  8
Affiliations
  • 1. EA GICC - ERL 7001 CNRS « Groupe Innovation et Ciblage Cellulaire », Team Innovation Moléculaire et Thérapeutique, University of Tours, F-37200, Tours, France.
  • 2. CNRS ERL7001 LNOx « Leukemic Niche and RedOx Metabolism » - EA GICC, University of Tours, F-37000, Tours, France; CHRU de Tours, Service d'Hématologie Biologique, F-37044, Tours, France.
  • 3. Université de Nantes, Nantes Atlantique Universités, Département de Chimie Thérapeutique, Cibles et Médicaments des Infections et du Cancer, IICIMED- EA1155, Institut de Recherche en Santé 2, F-44200, Nantes, France.
  • 4. UMR University of Orléans-CNRS 7311, Institut de Chimie Organique et Analytique (ICOA), University of Orléans, F-45067, Orléans, France.
  • 5. Sorbonne Universités, USR3151 CNRS/UPMC, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Station Biologique, Place Georges Teissier, F-29688, Roscoff, France.
  • 6. UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, University of Lille, Inserm, CHU Lille, F-59000, Lille, France.
  • 7. CNRS ERL7001 LNOx « Leukemic Niche and RedOx Metabolism » - EA GICC, University of Tours, F-37000, Tours, France.
  • 8. EA GICC - ERL 7001 CNRS « Groupe Innovation et Ciblage Cellulaire », Team Innovation Moléculaire et Thérapeutique, University of Tours, F-37200, Tours, France. Electronic address: [email protected].
PMID: 29778892 DOI: 10.1016/j.ejmech.2018.04.056
Abstract

We identified a new series of quinoxaline-2-carboxylic acid derivatives, targeting the human proviral integration site for Moloney murine leukemia virus-1 (HsPim-1) kinase. Seventeen analogues were synthesized providing useful insight into structure-activity relationships studied. Docking studies realized in the ATP pocket of HsPim-1 are consistent with an unclassical binding mode of these inhibitors. The lead compound 1 was able to block HsPim-1 enzymatic activity at nanomolar concentrations (IC50 of 74 nM), with a good selectivity profile against a panel of mammalian protein kinases. In vitro studies on the human chronic myeloid leukemia cell line KU812 showed an antitumor activity at micromolar concentrations. As a result, compound 1 represents a promising lead for the design of novel Anticancer targeted therapies.

Keywords
Anticancer targeted therapy; Kinase inhibitor; Pim-1; Quinoxaline.