A Personalized 14-3-3 Disease-Targeting Workflow Yields Repositioning Drug Candidates.

Area of Science:

• Genetics and Molecular Biology
• Drug Discovery and Development
• Rare Diseases

Background:

• Rare diseases present unique challenges for drug discovery due to limited understanding and small patient populations.
• The gene YWHAG, encoding the 14-3-3γ protein, is implicated in a pediatric neurological disorder when mutated.
• Pathogenic mutations in YWHAG lead to nuclear relocalization and impaired 14-3-3γ protein interactions.

Purpose of the Study:

• To establish a rare disease-directed workflow for rapid molecular characterization and drug repurposing.
• To identify and validate repositioning drug candidates for a pediatric neurological disorder linked to YWHAG mutations.
• To demonstrate the workflow's applicability to other 14-3-3-related disorders and rare diseases.

Main Methods:

• Developed a workflow to study rare disease molecular features and establish a high-throughput screening (HTS) platform.
• Conducted an HTS of approximately 3000 approved drugs to identify candidates for YWHAG-related disorders.
• Validated drug candidates that restore 14-3-3γ phosphotarget interactions disrupted by pathogenic YWHAG mutations.

Main Results:

• Identified nuclear relocalization and reduced 14-3-3γ binding as key molecular features of pathogenic YWHAG mutations.
• Screened ~3000 approved drugs, identifying potential repositioning candidates.
• Validated candidates that effectively restore deficient 14-3-3γ-phosphotarget interactions.

Conclusions:

• The developed workflow enables rapid identification of drug repositioning candidates for rare diseases.
• This approach is effective for YWHAG-related disorders and can be adapted for other rare conditions.
• The study highlights the potential of repurposing approved drugs for understudied genetic disorders.