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.

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