Validation of the target is the first critical step of a strong drug discovery program
A thorough validation of the mechanism of action of a target and/or a compound has been shown to play a vital role in the survival of a drug discovery program leading up to and through Phase Two clinical trials.
Target-based drug discovery has the benefit of focusing on one single activity for the optimization of the compounds and on a set of defined cellular events for functional readouts. Nonetheless, it is a reductionist approach where, as demonstrated by the recent history of target-based drug discovery programs, a poor validation of the target and/or drug mode of action can lead to unprecedented artefactual results.
We understand that target validation is the first and crucial step of drug discovery, and as a consequence it must be evaluated in the best and most human-relevant way possible. To do so, we use a combination of tools and strategies.
- Human relevance: it is now known that in vitro biological evidence of the activity of a target is very often hampered by potential artefactual conditions. To overcome this limitation, bone fide targets should be searched within human genomic data associated to clinical conditions.
- In vitro models: we take advantage of stem cells for modelling diseases exploiting their normal karyotype (when QC tested). They can be manipulated, differentiated to become the desired target tissue, and potentially sourced from diseased individuals for phenocopy studies.
- Functional/pharmaco-genomics: we apply standard genetic (by siRNA and genome modification) and pharmaco-genetic (by annotated compound testing) techniques to perturb relevant in vitro systems (see previous) in order to demonstrate target validity.
- Druggability: thanks to out extensive experience in drug discovery, we have a clear understanding on what targets have the best chance to be drugged. Regardless, we do not restrict ourselves to traditional strategies, as we have succeeded in drugging protein-protein interactions as well as using non-standard molecules (such as peptides) for tough intracellular targets.
Target validation is widely presented as the first step in drug discovery programs. Targeted projects have been questioned in the past, due to them not considering the complexity of a human being. We believe this not applicable when a thorough validation has been carried out in the light of the requirements of a clinically active modulator.