Rigorous scientific validation of a target of interest is a hugely important first step in the route to novel drug discovery. Inadequate pre-clinical target validation often leads to lack of efficacy and/or toxicity which then leads to the failure of drugs in development in the clinic.
Target identification and validation can usually take 2-6 months depending on the availability of tools and the target complexity. For example, target validation of a poorly studied target with multiple potential off-target liabilities takes longer than that of a well-studied target.
Target validation involves the application of a range of techniques that aim to demonstrate that drug effects on the target can provide a therapeutic benefit with an acceptable safety margin. Early in-depth target validation increases the understanding of target biology and in turn, the probability of success in the clinic.
Broadly, target identification uses methods of data mining from available databases and literature, and computational and pharmacophore models. Target identification is followed by target validation which can be divided into following steps
Target Expression
Data mining from disease relevant databases, experimental validation of target protein expression and function in the desired tissue or cell types and a thorough analysis of target mRNA and/or protein expression alteration in the disease state
Genetically Engineered Models
Develop target-based genetic knock-ins/outs cell lines and/or transgenic mice to validate target gene association with disease phenotype.
Efficacy and Biomarkers
The main objective of target validation is to ensure that the target has a clear role in the disease process. One of the important aspects of target validation is to show efficacy in clinically relevant animal models with modulation of signalling biomarkers that can be tracked in patients.
Once a target has reached an acceptable level of validation and disease linkage, the project then moves into the hit identification phase.
