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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 (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.
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https://hal.archives-ouvertes.fr/hal-03408667
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Submitted on : Wednesday, November 3, 2021 - 5:15:25 PM
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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, Elsevier, 2018, 154, pp.101-109. ⟨10.1016/j.ejmech.2018.04.056⟩. ⟨hal-03408667⟩

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