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

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

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: caroline.sabourin@univ-tours.fr.
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.

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