Structure-based optimization of oxadiazole-based GSK-3 inhibitors

Area of Science:

• Biochemistry
• Neuroscience
• Medicinal Chemistry

Background:

• Glycogen synthase kinase-3 (GSK-3) inhibition offers neuroprotection by reducing beta-amyloid and tau hyperphosphorylation, key factors in Alzheimer's disease (AD).
• GSK-3 has two mammalian isoforms, GSK-3α and GSK-3β, with highly similar catalytic domains, posing a challenge for selective inhibition.

Purpose of the Study:

• To investigate novel GSK-3 inhibitors based on distinct chemical scaffolds.
• To elucidate the structural requirements for binding within the ATP-binding pocket of GSK-3 isoforms.
• To evaluate the efficacy and safety of lead compounds in a relevant biological model.

Main Methods:

• Synthesis and characterization of GSK-3 inhibitors utilizing oxadiazole and benzodioxane scaffolds.
• Enzyme inhibition assays to determine IC50 values and selectivity for GSK-3α and GSK-3β.
• In vivo assessment of compound permeability and toxicity in wild-type zebrafish embryos.

Main Results:

• The oxadiazole scaffold yielded potent and selective GSK-3 inhibitors.
• Acetamide 26d (oxadiazole series) demonstrated high potency with IC50 values of 2 nM (GSK-3α) and 17 nM (GSK-3β).
• Benzodioxane 8g exhibited significant selectivity for GSK-3α over GSK-3β (27-fold), with an IC50 of 35 nM for GSK-3α.

Conclusions:

• Novel GSK-3 inhibitors targeting the ATP-binding pocket were successfully developed.
• Specific scaffolds, particularly oxadiazole, are effective in generating potent and selective inhibitors.
• Initial in vivo profiling in zebrafish embryos provides a basis for further development of GSK-3 inhibitors for potential therapeutic applications in neurodegenerative diseases like AD.