Research ArticleCancer

Exploiting an Asp-Glu “switch” in glycogen synthase kinase 3 to design paralog-selective inhibitors for use in acute myeloid leukemia

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Science Translational Medicine  07 Mar 2018:
Vol. 10, Issue 431, eaam8460
DOI: 10.1126/scitranslmed.aam8460

The right GSK for the job

The enzyme glycogen synthase kinase 3 (GSK3) has been proposed as a potential therapeutic target in many diseases, but none of the drugs targeting this enzyme so far have translated to the clinic. A major reason for this failure to translate is the existence of two closely related paralogs of GSK3 such that most drugs target both forms at once and cause unacceptable toxicity. By applying a rational structure-based approach, Wagner et al. were able to design selective inhibitors for the α and β isoforms of this enzyme and then show that selective GSK3α inhibitors specifically show promising activity against acute myeloid leukemia with no detectable effects on healthy hematopoietic cells.


Glycogen synthase kinase 3 (GSK3), a key regulatory kinase in the wingless-type MMTV integration site family (WNT) pathway, is a therapeutic target of interest in many diseases. Although dual GSK3α/β inhibitors have entered clinical trials, none has successfully translated to clinical application. Mechanism-based toxicities, driven in part by the inhibition of both GSK3 paralogs and subsequent β-catenin stabilization, are a concern in the translation of this target class because mutations and overexpression of β-catenin are associated with many cancers. Knockdown of GSK3α or GSK3β individually does not increase β-catenin and offers a conceptual resolution to targeting GSK3: paralog-selective inhibition. However, inadequate chemical tools exist. The design of selective adenosine triphosphate (ATP)–competitive inhibitors poses a drug discovery challenge due to the high homology (95% identity and 100% similarity) in this binding domain. Taking advantage of an Asp133→Glu196 “switch” in their kinase hinge, we present a rational design strategy toward the discovery of paralog-selective GSK3 inhibitors. These GSK3α- and GSK3β-selective inhibitors provide insights into GSK3 targeting in acute myeloid leukemia (AML), where GSK3α was identified as a therapeutic target using genetic approaches. The GSK3α-selective compound BRD0705 inhibits kinase function and does not stabilize β-catenin, mitigating potential neoplastic concerns. BRD0705 induces myeloid differentiation and impairs colony formation in AML cells, with no apparent effect on normal hematopoietic cells. Moreover, BRD0705 impairs leukemia initiation and prolongs survival in AML mouse models. These studies demonstrate feasibility of paralog-selective GSK3α inhibition, offering a promising therapeutic approach in AML.

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