Attrition levels in drug discovery remain high, with almost 60% of candidate drugs failing during clinical development due to insufficient efficacy. These failures have costly consequences for pharmaceutical and biotech companies. As well as gaining no return on their investment, investigations into the target are typically halted, which limits the organization’s portfolio development and can impact their market share. What’s more, for smaller companies investing in only one asset, efficacy failures can mean they have to close altogether.
One way that companies can try to avoid these late stage failures and associated costs is to better predict the efficacy of the candidate drug using more relevant target engagement assays. This should be assessed early in the drug discovery project to anticipate failure well before a candidate drug is selected for clinical trials. These tests can assess whether the compounds bind to the intended site of action on the target protein. As a key indicator of the drug’s efficacy, it’s imperative that the target engagement assays used provide reliable assessments of drug-target binding.
Recent developments enable more relevant target engagement assessments in the earliest stages of drug discovery. Below, we explore how you can start changing the way target engagement is measured during your lead generation and lead optimization studies. Adopting novel methods can ensure you achieve your goals and accelerate your team ahead of your competitors, while ensuring you develop compounds that will become vital new drugs for patients.
Measuring target engagement for drug discovery: A change for the better
In drug discovery programs, target engagement assays are vital tools for identifying which compounds to prioritize for further investment. However, the high rate of efficacy failures during clinical development suggests that current target engagement assays are not working as well as they should.
One key reason for the poor rate of success is that conventional target engagement assays do not sufficiently replicate the therapeutic action of the drug within the patient’s body. For example, traditional cell-based approaches often use artificial substrates and can involve the modification of compounds and targets using synthetic tags or labels. What’s more, recombinant purified protein-based assays such as surface plasmon resonance (SPR) only measure drug binding on immobilized proteins in an isolated cell-free environment. As such, these conventional assays don’t sufficiently mimic the in vivo environment.
As a result, conventional target engagement assays increase the risk that you will prioritize ineffective compounds, at great cost to your company as well as to your own goals. What’s more, if the majority of companies continue to use these traditional methods, then the high attrition rate in drug discovery will continue unabated.
It’s clear that a change is needed in the industry to improve the current situation—fortunately, there is already one promising solution.
How can a novel target engagement assay revolutionize your research?
One way to overcome the challenges posed by traditional target engagement assays is to adopt an innovative method: The Cellular Thermal Shift Assay (CETSA®). This measures target engagement within the natural environment of living intact cells, lysates, and even tissues, without modifying the compounds or target proteins. Invented in 2012, CETSA leverages the basic principle of thermal shift assays, with the novel insight that the melt curves of proteins can be measured in living cells.
Compared to conventional biophysical approaches, this label-free measure of affinity offers a more accurate, direct measurement of drug-target binding in a more physiologically relevant manner. As such, CETSA gives you true target engagement potencies, enabling you to make more reliable predictions of efficacy. What’s more, it can speed up your project timelines by 6-12 months and allows you to rapidly translate target engagement data between different cells and tissues.
CETSA is also available in three formats. These provide additional flexibility, as they allow the assay to be applied at any stage of drug discovery, including in early lead generation as well as in later lead optimization. The three formats are:
- CETSA Classics for lead optimization: The earliest developed format. This uses a Western blot detection method and is valuable for screening a handful of compounds in low-throughput and translational studies. This tool provides unique benefits in lead optimization studies, such as directly assessing drug binding in in vivo animal experiments.
- CETSA HT for lead generation: First developed in 2016, this microtiter plate-based format is highly effective for high-throughput screening of >10,000 compounds (and potentially >100,000). This is already helping to advance lead generation studies, including identifying novel compounds against important cancer targets.
- CETSA MS: An unbiased, proteome-wide method leveraging mass spectrometry. This recently developed approach has already shown promise in Mechanism-of-Action (MoA) studies, as well as in phenotypic target deconvolution and safety assessments.
By enabling you to make confident prioritization decisions at a discovery stage as early as lead generation, CETSA helps you avoid the risk of investing in the wrong compounds and ensures you progress only the very best compounds through the pipeline.
Achieve your goals and get ahead by embracing novel methods
Leading pharmaceutical and biotech companies are already prospering from the many benefits CETSA can bring to lead generation and lead optimization studies. Embracing change by adopting such novel methods can provide you with high-quality, relevant data for making better-informed prioritization decisions, so that you invest in only the best compounds. Not only will this allow you to accelerate ahead of your competitors, but by progressing only the very best compounds, you will also be helping to reduce attrition in drug discovery and bring essential new treatments to patients.