Somatic alterations in the oncogenic kinase AKT1, particularly the E17K mutation, induce constitutive activation of AKT signaling, prompting the urgent need for targeted therapeutic strategies.
The design of allosteric, lysine-targeted salicylaldehyde inhibitors has shown promising selectivity for AKT1 E17K over wild-type AKT, illustrating a significant advancement in targeted cancer therapy.
Crystallographic analysis revealed an unexpected tetrahedral zinc ion in the covalent inhibitor complex, highlighting intricate molecular interactions that enhance the specificity of inhibitors for AKT1 E17K.
In xenograft models, salicylaldehyde-based inhibitors demonstrated efficacy against AKT1 (E17K) tumors without inducing hyperglycaemia, underscoring their therapeutic potential and safety.
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