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

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 (1) , Marie-Claude Viaud-Massuard (1) , Caroline Denevault-Sabourin (7)

1 GICC EA 7501 - Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-.2022]
2 LNOx - ERL 7001 LNOx (Leukemic Niche & redOx metabolism / Niche leucémique et métabolisme redOx)
3 IICiMed - Cibles et Médicaments des Infections et de l'Immunité - EA 1155
4 ICOA - Institut de Chimie Organique et Analytique
5 P3H - Phophorylation de protéines et Pathologies Humaines
6 JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837
7 IMT - GICC EA 7501, IMT (Innovation moléculaire et thérapeutique)

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.

Mots clés: Anticancer targeted therapy; Kinase inhibitor; Pim-1; Quinoxaline; Anticancer targeted therapy

Domaines: Chimie thérapeutique; Cancer

Bruno Oyallon, Marie Brachet-Botineau, Cédric Logé, Pascal Bonnet, Mohamed Souab, et al.. Structure-based design of novel quinoxaline-2-carboxylic acids and analogues as Pim-1 inhibitors. European Journal of Medicinal Chemistry, 2018, 154, pp.101-109. ⟨10.1016/j.ejmech.2018.04.056⟩. ⟨hal-03408667⟩