The multiple orthogonal tools approach to define molecular causation in the validation of druggable targets

Area of Science:

• Genetics
• Epigenetics
• Immunology
• Pharmacology

Background:

• High-throughput target validation is crucial for novel drug discovery, often employing genetic and epigenetic methods.
• Current approaches frequently rely on loss-of-function studies, which may not provide comprehensive validation.
• Initiating drug discovery projects based on correlative evidence is common but less definitive than causative evidence.

Purpose of the Study:

• To emphasize the importance of orthogonal approaches in target validation.
• To highlight the limitations of relying solely on loss-of-function studies.
• To advocate for the integrated use of multiple methods for robust drug target validation.

Main Methods:

• Application of genetic methods (gene deletion, interruption, mutation).
• Utilization of epigenetic methods (antisense RNA, small interfering RNA).
• Integration of immunological methods and other orthogonal tools.

Main Results:

• Orthogonal approaches provide more reliable target validation than single methods.
• Correlative evidence allows for faster project initiation but requires further validation.
• Robust in vivo efficacy testing necessitates simultaneous application of multiple orthogonal tools.

Conclusions:

• Multiple orthogonal approaches are essential for reliable high-throughput target validation.
• Combining diverse methods strengthens the evidence for a drug candidate's efficacy and target engagement.
• The orthogonal tools approach is critical for rigorous drug discovery and development.