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Target Validation is the foundation of your investment decisions. Here’s how to do it right.

You are standing at a crossroads, and each potential target marks a different road.

The further you move down any path, the more resources you use, and the more it will cost to start again – both financially and timewise.

This is why choosing the right target before embarking on a drug discovery programme, and continuing to validate that target throughout the journey, is arguably the most critical part of the drug discovery process.

Ultimately, target validation (TV) can give confidence to clients to increase investment into a particular project, or save them time and capital by ‘invalidating’ a target quickly and robustly.

The reality is, if the wrong target is chosen, it doesn’t matter how elegant and safe the therapeutic agent is in pre-clinical studies, it will never succeed in phase 3 clinical trials. Therefore, investing the right amount of focus and resources on this process at the start, and throughout the project, is a sound long-term strategy for any pharmaceutical or biotech company.


A Roadmap to Good Target Validation:


1. TV starts with, and ends with, the clinic

The question should always be in our minds: is there a testable hypothesis that can be investigated in a clinical trial?

Many project teams believe that TV happens at project inception, but it should be a continual process, all the way through to marketing authorisation. As our understanding grows, and tool compounds improve, the detail of the TV experiments can improve to continually interrogate our disease linkage and target understanding. Ultimately, this continual re-examination of our new target will increase our chances of clinical success and delivering patient benefit, which should always be our focus in drug discovery.


2. Thorough understanding of the biology of the target

Understanding the molecular networks underpinning the pathogenesis of disease is central to this process. In order to narrow in on the most relevant target in that pathway, you must first build a detailed comprehension of the whole network. No shortcuts.

While this statement seems daunting (and often discourages researchers from undertaking projects on novel targets), we should not shy away from the challenge of less conventional targets, as an ever-growing set of therapeutic modalities enable us to target non-enzyme, non-receptor proteins as well as RNA and DNA.

Just because there is a broken protein doesn’t mean it is the right point of intervention, and just because it’s the easy target doesn’t mean it’s the right one. This is why we believe in partnering with our client to fully understand the disease biology and build a contextual picture.

Often the best way for a client to achieve this goal is through building of a network of collaborators in academia and industry that covers expertise across all aspects of the target. This interdisciplinary approach brings together varied and valuable expertise to ensure the best possible project decisions are made and actioned.


3. Use complimentary approaches that mirror the therapeutic modality

Understanding the specific role of a target in human disease is not always as straightforward as we like to imagine. To better understand this, scientists often rely on gain- and loss-of-function studies to validate a target, but these studies do not always phenocopy the effect induced by a small-molecule inhibitor/activator.

So, it’s important to combine several complimentary experimental approaches that mimic the therapeutic modality, to overcome each other’s limitations and strengthen the data package. For example, genetic methods can be used to introduce precise inhibitory or activating mutations in the protein and investigate their effect in cellular and animal systems. Unfortunately, these changes to the genome are permanent, and prevent the temporal analysis of modulating the function of the target. Alternatively, chemical probes can be used for target validation as they directly mimic the therapeutic approach. However, these molecules are often non-selective, and this complicated pharmacology can often complicate data interpretation. In these circumstances, the generation of a drug-resistant mutant can provide strong evidence of the ability to drug a specific target for the therapeutic indication of choice.


4. Appreciate the source and limitations of each experiment, but never ignore data

The scientific literature is vast and, rather than providing clarity, it often raises more questions than answers, with conflicting hypotheses and conclusions around the disease relevance of an emerging target.

This is where it is important to have confidence in your own data rather than blindly rely on the literature, and to build a robust package of data to support clinical application. If, however, the internal data does not support a particular target, it is critical to invalidate it as early as possible in the drug discovery process to save on valuable resources.


5. Commitment and investment

All projects have limited resources, and managing and apportioning them is a challenging part of a clients’ journey. From experience we have seen that when budgets are drawn up, TV can be an area that suffers. The unfortunate result is that inappropriate budget and manpower can force those running the TV process to cut corners and generate a data package that is weaker than it should be.

While this can be an appealing way to save resources in the present, in the long run, weak data is more costly than making the right commitment at the start.


The target validation process is foundational to drug discovery programmes, and is especially pertinent for start-ups with their first round of funding, where we have demonstrated our ability to add tremendous value to clients at this critical stage of drug discovery (see our case study with CellCentric here) and help them use their investments effectively to understand if their target has the legs to go all the way and secure Series A and B funding.

In the end, no matter who the client is or what human disease we are confronting, the best therapeutic strategy will be born of a holistic approach which incorporates biochemical, cellular, genetic, and pharmacological methodologies.

Our integrated approach at Sygnature is built on clear communication and collaboration with our clients, with others we may partner with for specialist knowledge or services, and importantly within our own departments – where we bring in different minds, different expertise and methodologies to help us think creatively and solve problems.

The interaction between chemistry and bioscience at Sygnature leads to an evolving process that continues to revalidate the target and improve the data package. As the compounds get better and better, the biology clarifies and strengthens, and that allows us to collectively think more about patient stratification and how to apply it in a clinical trial, which is always our endgame.

If you would like to discuss target validation, our capabilities, or what we are about, then we’d love to hear from you. You can get in touch by using any of the contact forms.