Tackling this ongoing problem is crucial. Fortunately, developments in assays are enabling more reliable efficacy predictions during the early stages of the drug discovery pipeline. As we discuss in our new eBook, this can help you to make confident prioritization decisions and progress only the very best compounds from the start of your project.Download our new eBook: “Enhance your Drug Discovery using CETSA: Can you afford not to?” Read on to find out more about how adopting a novel approach can enhance your drug discovery projects. This will not only help you to achieve your goals, but also reduce attrition in drug discovery and meet society’s significant need for new therapeutics.
Efficacy failures in drug discovery: diagnosis and treatment
Almost 60% of failures in drug development are caused by inadequate efficacy. This shows that current methods aren’t reliably identifying which compounds are likely to succeed or fail – a costly problem for the industry. Late stage failures result in a substantial loss of resources for pharmaceutical and biotech companies. As a result, they might be forced to stop investigations into that asset at great cost to their development portfolio, which can have severe consequences for their existing market share. For smaller companies, this can ultimately result in their closure.
So why is the failure rate so high? To assess whether a drug will be effective, measurements are taken to determine how the compound binds at the intended site of action, a process known as target engagement. However, traditional assays used for these measurements are not conducted under physiological conditions, so target engagement values are unlikely to correlate with what happens physiologically in the patient. As target engagement is a critical requirement for efficacy, it’s no wonder that clinical trials are plagued with a high rate of failure due to poor efficacy.
It is clear that rigorously confirming target engagement under physiological conditions should be a prerequisite for progressing compounds through to pre-clinical phases. But rather than using this approach to simply confirm the outcome of lead optimization, it would be much more efficient to apply it earlier, during the lead generation stage. After all, while it might be useful to know that your medicinal chemistry has lost its way, isn’t it better not to get lost in the first place?
Fortunately, recent developments are now enabling more physiologically relevant measurements of target engagement that can drive your efficacy predictions from the earliest lead generation phase of your programs.
Using novel tools to better predict efficacy outcomes in drug discovery
The Cellular Thermal Shift Assay (CETSA®) is a novel way of measuring target engagement within more relevant physiological material, including live cells, based on the fundamental principle of thermal shift assays. As it is a label-free method, compounds and target proteins are unmodified and so remain in their natural state. Also, by generating more relevant data, CETSA can speed up project timelines by up to one year compared to traditional assays.
CETSA is an extremely flexible assay that can be used to study target engagement in a variety of relevant physiological material, including live cells, lysates and even tissue samples, at any stage of drug discovery. The proof of concept experiment introduced CETSA using a Western blot method, known as the ‘CETSA Classics’ format. This has established its value for confirming target engagement in a handful of compounds, which is enhancing lead optimization as well as animal and human translational studies.
A newer ‘CETSA HT’ microtiter-based format now also allows the assay to screen more than a handful of compounds and so can be applied as early as lead generation. This format has the powerful ability to screen >10,000 compounds (and potentially >100,000) and can help to identify existing as well as novel compounds that other traditional assays miss.
However, as CETSA has only been available for six years, it is not yet widely used. This is likely because many scientists understandably prefer to use established methods to offset the high-risk nature of drug discovery. But several leading pharmaceutical and biotech companies are adopting CETSA, and it is already advancing lead generation and lead optimization studies to help boost drug discovery success
Why not seize the opportunity for success and adopt CETSA?
Only six years after it was introduced, CETSA has already made a significant impact on the scientific community and has stimulated the advancement of drug discovery. Not only will the benefits of using CETSA help you to hit key project milestones and stay under budget, but it will also ensure you progress only the most effective compounds to the next stage of drug discovery. By embracing new techniques such as CETSA together, we can help reduce high attrition rates and get more drugs to patients quicker to improve their quality of life.Download the free eBook to learn how CETSA can enhance your drug discovery