Elucidation of the GSK3α Structure Informs the Design of Novel, Paralog-Selective Inhibitors.

ABSTRACT: Glycogen synthase kinase 3 (GSK3) remains a therapeutic target of interest for diverse clinical indications. However, one hurdle in the development of small molecule GSK3 inhibitors has been safety concerns related to pan-inhibition of both GSK3 paralogs, leading to activation of the Wnt/β-catenin pathway and potential for aberrant cell proliferation. Development of GSK3α or GSK3β paralog-selective inhibitors that could offer an improved safety profile has been reported but further advancement has been hampered by the lack of structural information for GSK3α. Here we report for the first time the crystal structure for GSK3α, both in apo form and bound to a paralog-selective inhibitor. Taking advantage of this new structural information, we describe the design and in vitro testing of novel

SUBMITTER: Amaral B 

PROVIDER: S-EPMC10020971 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature