Effective validation of drug targets: an interview with Lyn Jones
In this interview with Lyn Jones (Jnana Therapeutics, MA, USA), learn more about the importance of validating drug targets and recent advancements to aid this.
Why is it important to ensure drug targets are validated before proceeding with research / clinical trials?
Most drug development fails in Phase II clinical trials, when the mechanism under investigation is usually tested in patients for the first time. Sometimes a target is chosen that doesn’t have the requisite horsepower and sometimes the candidate drug simply doesn’t engage the target sufficiently. Higher confidence in a target, and that the candidate will effectively engage that target in patients, will likely translate to higher success rates in drug development.
What processes does a target undergo to become fully validated?
Functional gene knock-down screens in disease-relevant cell-based assays are a great starting point to identify potentially interesting targets. Validation of those target hits may require more bespoke and specialized experiments, ideally in patient-derived cells/tissues or in vivo studies in animal models. However, the pharmacological modality must also be validated – for example, does an ATP-competitive kinase inhibitor phenocopy CRISPR-Cas9 modulation? Some targets are already validated, such as those associated with Mendelian diseases, so the emphasis here is more about building confidence in the therapeutic modality. Another key aspect of target selection is safety, which contributes to risk-benefit considerations.
In my opinion it is unlikely that target validation can be done comprehensively by a single group/company. For instance, chemical probes should be made open access to the broader scientific community to help develop a deeper understanding of possible therapeutic targets.
In your opinion, what has been the biggest recent advancement to aid drug target validation?
Chemical biology is more embedded now in drug discovery than it has ever been, particularly in the area of molecular pharmacology. For example, chemical biologists have developed new technologies that are able to quantify drug-target engagement and selectivity in live cells, and then correlate this to functional effects in vivo – the earlier you can do this in drug discovery research and development the better. More needs to be done though to break down siloed disciplines in pharmaceutical research, particularly in big pharma, to enable multidisciplinary teams to focus on the questions that really matter. Increasingly, new biotech companies place chemical biology front and center as a key strategy to identify and validate new therapeutic targets.
Where do you think the technology is likely to go in the future?
Disease needs to be redefined at the molecular level, rather than rely on outdated modes of diagnosis based on gross pathology. Technologies are required that develop our understanding of molecular etiology, leading to more precise drug discovery strategies and more successful target selection.
Appropriate biomarkers need to be developed that show the drug is acting in the way predicted from preclinical experiments. In both of these areas, which are central to successful translational pharmacology, integrated omic technologies, such as chemoproteomics, transcriptomics and metabolomics, will play increasingly important roles in the future.
How can computational techniques aid drug target validation?
Computational techniques are used to integrate various omic and genetic association data to generate systems level understanding, which is required to provide confidence that target modulation will affect disease. Additionally, bioinformatics analyses are required to leverage public and private data collections to select appropriate pharmacological tools to validate a target or to create chemogenomic compound libraries for use in phenotypic screens, which can expedite target identification.