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

• DOI: 10.1016/j.ejmech.2018.04.056
• Publication Date: 2018-05-11T06:56:00Z
• Authors: Bruno Oyallon; Marie Brachet-Bot...; Cédric Logé; Pascal Bonnet; Mohamed Souab; Thomas Robert; Sandrine Ruchaud; Stéphane Bach; Pascal Berthelot; Fabrice Gouilleux; Marie-Claude Viau...; Caroline Denevaul...
• Keywords: Quinoxaline; Lead compound; Docking (animal); Structure–activity relationship; IC50

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.