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

Abstract We identified a new series of quinoxaline-2-carboxylic acid derivatives, targeting the human proviral integration site for Moloney murine leukemia virus-1 ( Hs Pim-1) kinase. Seventeen analogues were synthesized providing useful insight into structure-activity relationships studied. Docking studies realized in the ATP pocket of Hs Pim-1 are consistent with an unclassical binding mode of these inhibitors. The lead compound 1 was able to block Hs Pim-1 enzymatic activity at nanomolar concentrations (IC 50 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.