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

  • Pharmacie,

du 12 novembre 2018 au 31 décembre 2018


Site Grandmont

Faculté de Pharmacie- Philippe Maupas

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.

quinoxaline; Pim-1; kinase inhibitor; anticancer targeted therapy.

Authors :
B. Oyallon, M. Brachet-Botineau, C. Logé, P. Bonnet, M. Souab, T. Robert, S. Ruchaud, S. Bach, P. Berthelot, F. Gouilleux, M.-C. Viaud-Massuard, C. Denevault-Sabourin*, Eur. J. Med. Chem. 2018, 154, 101-109.