Drug Development.

Area of Science:

• Neuroscience
• Pharmacology
• Molecular Biology

Background:

• Alzheimer's disease (AD) involves impaired histone acetylation and Wnt/β-catenin signaling.
• Targeting multiple pathologies, like with dual modulators, may offer synergistic effects for AD.
• Class I histone deacetylase (HDAC) inhibitors and Wnt/β-catenin pathway activators are potential AD therapeutics.

Purpose of the Study:

• To develop novel dual modulators targeting class I HDAC inhibition and Wnt/β-catenin signaling activation.
• To evaluate the therapeutic potential of the lead compound W2A-28 in Alzheimer's disease (AD) models.

Main Methods:

• Utilized CI-994 as a scaffold to design dual-acting compounds.
• Assessed W2A-28's inhibitory activity against class I HDACs and its effect on Wnt reporter activity.
• Determined W2A-28's impact on LRP6 protein levels, solubility, stability, and permeability.
• Tested W2A-28 in patient-derived induced pluripotent stem cell (iPSC)-derived cerebral organoids.

Main Results:

• W2A-28 potently inhibited class I HDAC1, 2, and 3 with nanomolar IC50 values.
• W2A-28 activated Wnt/β-catenin signaling by increasing Wnt reporter activity and stabilizing LRP6.
• The compound exhibited favorable pharmacokinetic properties, including good solubility, stability, and permeability.
• W2A-28 significantly reduced amyloid-beta (Aβ40, Aβ42) levels and suppressed tau phosphorylation in AD organoids.

Conclusions:

• W2A-28 demonstrates dual inhibitory and activating properties relevant to AD pathology.
• The compound effectively reduced key Alzheimer's disease biomarkers in patient-derived organoids.
• W2A-28 represents a promising drug candidate for Alzheimer's disease treatment.