Discovery of novel glycogen synthase kinase-3 alpha inhibitors: Structure-based virtual screening, preliminary SAR and biological evaluation for treatment of acute myeloid leukemia

摘要

Glycogen synthase kinase 3 alpha (GSK-3 alpha) plays a constitutive role in various physiological processes and has been proved to be a therapeutic target for acute myeloid leukemia (AML). In this paper, by means of computer-aided drug design, we discovered a novel chemical series of GSK-3 alpha inhibitors with an IC50 value of 0.033-2.804 mu M. The preliminary structure-activity relationship was concluded and, notably, the most potent and isoform-selective compound G28_14 was identified with IC50 values of 33 nM and 218 nM against GSK-3 alpha and -3 beta, respectively, exhibiting a nearly ten-fold isoform-selectivity. Further cell viability assays and colony formation assays revealed that G28_14 suppressed cell survival by impairing cell proliferation by up to 90% in two AML cell lines. Moreover, surface marker expression analysis demonstrated that G28_14 induced terminal differentiation with a high level of CD11b, CD11c, and CD14. Western immunoblotting showed that G28_14 isoform-selectively inhibited the phosphorylation of GSK-3 alpha in-cell without activating Wnt/beta-catenin signaling. In addition, to elucidate its structure-activity relationship, the binding mode of this chemical series was proposed using molecular docking and molecular dynamics simulations. Taken together, this chemical series is worth developing as differentiation therapies for the treatment of AML. (C) 2019 Elsevier Masson SAS. All rights reserved.