Finding effective drugs to improve patients’ lives is one of the most important challenges facing society today. However, drug development is beset by a high rate of efficacy failure in clinical trials. This is not only limiting the rate of new drug approvals, but it is also considerably costly for pharmaceutical and biotech companies. Late-stage failure means companies receive no return on their investments and may have to end investigation into a target altogether, at great cost to their portfolio development and market share. Smaller companies may even have to close altogether if their only asset fails.

So, what’s causing costly efficacy failures and what can we do about it? As we discuss in our new eBook, one promising solution is to adopt better ways of predicting clinical efficacy during lead generation and lead optimization to ensure that only the most promising drug candidates are progressed to clinical trials.

Learn more about the importance of adopting novel approaches in drug discovery to improve efficacy success

Read on to find out how novel approaches to predicting efficacy can help tackle challenges in lead optimization, which can help prevent costly late-stage efficacy failures and bring important new drugs to patients.

Lead optimization in drug discovery: Time for a rethink?

Each stage of drug discovery has its own challenges, and lead optimization is no exception. This stage is renowned for being highly complex, requiring multiple time-consuming assays to optimize the safety and efficacy of lead compounds.

For example, in lead optimization the compound design is based on structure-activity relationships analyses and requires assessment of drug metabolism and pharmacokinetics (DMPK) . These data help to refine the initial lead series into an even smaller set of special interesting compounds (pre-candidate drugs) that are subsequently passed to late lead optimization. At this stage, this smaller set of compounds is subjected to further rigorous tests, such as in vivo animal studies assessing pharmacokinetic and pharmacodynamic (PK/PD) properties for dose predictions.

Target engagement assays, which measure whether a drug binds to the intended target, are also routinely used during lead optimization to estimate efficacy of the compounds. However, with almost 60% of drugs failing in clinical trials due to poor efficacy, this indicates that conventional target engagement assays are not reliably distinguishing between effective and ineffective compounds.

One key reason for this is that conventional assays measure target engagement indirectly or artificially using synthetic labels or tags, so they do not sufficiently mimic how a compound will act in the patient’s body. Unfortunately, this increases the risk that your candidate drugs will fail during clinical trials.

What’s more, conventional target engagement assays can be extremely time-consuming. For example, cell-based chemical probes can involve up to a year of assay development, and each probe needs to be laboriously reconfigured for each new project. This can jeopardize your project deadlines, as well as incur unexpected costs that your budget cannot cover, making it difficult to ensure the quality of the compounds you progress down the pipeline.

Fortunately, recent developments are helping to overcome these issues by enabling quicker and more reliable efficacy predictions to enhance your lead optimization studies.

How modern tools can enhance lead optimization in drug discovery

Six years ago, a seminal experiment showed how the novel Cellular Thermal Shift Assay (CETSA®) can measure drug-target engagement in a physiologically relevant living cell and tissue environment. As such, CETSA generates more relevant target engagement data than conventional assays to provide more reliable efficacy predictions.

The assay can also be used to correlate target engagement in the cell with functional readouts, helping to understand the structure-activity relationship and strengthen the target validation before starting lead optimization. In this way, CETSA can help ensure your projects remain on track and enables you to prioritize only the very best compounds, thereby minimizing the risk of costly late-stage efficacy failures.

Three CETSA formats have been developed to enable the assay to be flexibly applied at any stage of drug discovery. The ‘CETSA HT’ microtiter plate-based format enables high-throughput assessments of >100,000 compounds during lead generation, and the ‘CETSA MS’ format leverages mass spectrometry for proteome-wide analysis. The third and earliest format, ‘CETSA Classics’, uses Western blot-mediated detection and is particularly valuable in lead optimization studies.

Leveraging the power of CETSA Classics for lead optimization

Various studies have shown the value of CETSA Classics in interrogating small numbers of compounds in low-throughput and translational studies, such as those performed during lead optimization. In translational studies, the CETSA EC50 values provide a constant reference point, enabling the direct comparison of target engagement in different cell and tissue samples. Indeed, a recent study has shown how CETSA Classics can directly monitor drug-target engagement in mouse peripheral blood, as well as spleen and brain tissue, highlighting its useful application in in vivo animal studies during lead optimization.

But this isn’t the only advantage of using CETSA Classics in your lead optimization studies. They are relatively simple experiments and take just one day to perform, so you can easily speed up your project timelines and minimize delays.

Adopt CETSA and lead the fight against attrition in drug discovery

Drug discovery is renowned for being a risky business due to the high likelihood of costly late-stage failures. This is in large part because of the limitations of conventional target engagement assays. However, recent innovations mean you no longer must rely on these traditional approaches. You can now easily use CETSA to generate more relevant target engagement data early in the pipeline. This data enables you to confidently prioritize only the most efficacious compounds from the outset, thus increasing the chances of success in clinical trials to ultimately give patients the drugs they need. So why not start reaping the benefits that CETSA can bring to your drug discovery programs?

Download your free copy of our new eBook to learn more about how CETSA can help you get ahead in drug discovery.