The hunt for selective drugs
How do you ensure that a drug has an effect on the right protein – and nothing else? Chemist Anthe Janssen explored various methods for determining the selectivity of potential medicines. He also looked at the substance BIA 10-2474, after a man died in a French clinical trial in 2016. PhD defence on 1 May.
‘The body is an amazingly complex whole. If you start pushing buttons, all sorts of things can go wrong.’ That makes selectivity so important in the hunt for new drugs, Anthe Janssen explains. ‘Selectivity means that your drug candidate controls or changes the right target protein in the right way, which means you adjust the right process in the body and don’t start pushing the wrong buttons.’ In an ideal world, a drug is so selective that it only binds to or has an effect on the target protein, but drugs often also have an effect on other molecules in the body. These are called off-targets. ‘Sometimes this isn’t a problem, but it can also produce undesirable effects. Take the side-effects of chemotherapy – these are because the chemo medication also has off-targets,’ says Janssen.
When developing new medicines, you obviously want to know if a promising molecule has any dangerous off-targets. ‘Large pharmaceutical companies therefore test candidate drugs as a default on a bunch of important proteins in the body, for instance those involved in the heart rate, to ensure they don’t also bind to these.’ For his PhD research, Janssen tested another technique: activity-based protein profiling (ABPP). ‘You can use this to test several proteins at a time and in a more lifelike environment than the pure protein tests that pharmacists use,’ Janssen explains. ‘I used this to look for possible inhibitors of the endocannabinoid system, which is involved in pain sensation and inflammation. This delivered good results: it’s a valuable technique.’
Study of French trial
And then came the clinical trial in France with its dramatic ending. The compound studied, BIA 10-2474, was supposed to inhibit FAAH, a protein that is also involved in the endocannabinoid system. The potential new painkiller was tested on healthy volunteers – and proved to have very serious neurological side-effects. One person died and a number of volunteers suffered such serious damage that they spent months recovering. Janssen: ‘On hearing the news, we immediately thought it would be off-targets that had caused the side-effects, and that we might be able to find them.’ One day later, he was in his lab reproducing BIA 10-2474, so that he would be able to use ABPP to look for these off-targets.
Red flags discovered
Janssen and his team, led by Mario van der Stelt, managed to track down a significant number of off-targets of the compound. ‘We were not able to demonstrate a causal link between exactly those off-targets and the serious side-effects – we didn’t test it clinically. But certain proteins were warning signals, proteins that you don’t want candidate drugs to have an effect on,’ says Janssen. ‘If the researchers from the trial had first tested the compound with ABPP and had known this, I don’t think they would have ever tested on healthy volunteers.’
However, it isn’t that surprising that they didn’t, Janssen explains. The method is about 20 years old – relatively young in the chemical world – and has not yet taken root. ‘It is mainly used in the academic world, but it is gradually gaining more attention – also inspired by our research into BIA 10-2474 of course.’ A good development, says Janssen. ‘Selectivity is the biggest challenges in drug development, and ABPP is a promising technique for testing the selectivity of candidate drugs.’
Text: Marieke Epping
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