. A unique type of GSK-3 inhibitor brings new opportunities to the clinic. Sci Signal. 2016 Nov 15;9(454):ra110. PubMed.


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  1. This exciting work from Licht-Murava and colleagues reveals a unique mode of inhibition of GSK3, using a peptide scaffold that acts as both a substrate and inhibitor through a kinase activity-dependent, “dissociation-resistant” conversion.

    Besides elucidating the mechanism of action of L807mts both in vitro and in cellular assays, an impressive aspect of the study is the in vivo data further demonstrating efficacy of selectively targeting GSK-3 in the context of preclinical models of neurodegeneration. This is a longstanding interest in the field that has been hampered by suboptimal pharmacological agents. 

    Further optimization of the pharmacological properties of L807mts to address potency and brain exposure has tremendous potential to advance novel therapeutic agents for Alzheimer’s and related neuropsychiatric disorders. One wonders if this method could be used for obtaining selective GSK3-α versus GSK3-β inhibitors, as well as inhibitors that show cell- or circuit-specific functional selectivity due to variation in the endogenous substrate concentration.

    Overall, these findings have important implications for designing selective probes of a number of kinases through the concept of substrate-to-inhibitor conversion mechanism.

    View all comments by Stephen Haggarty

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