Covalent drug resurgence: what’s the story?

The idea of designing drugs that form covalent bonds with their targets first emerged in the 1980s, but fell out of favour because of concerns about non-selective binding and the side-effects this might cause.

In recent years, there has been a surge in interest once more, and numerous partners are engaging us to work on covalent drug projects.

And why is that?

The concept of the covalent drug is, on the face of it, compelling. Most drugs bind reversibly to their target, so may not block the target for very long, depending on how fast the interaction reverses. A covalent drug forms a more permanent bond, potentially giving a much longer duration of action. One dose should be sufficient to saturate the target.

However, it soon became clear that selectivity could be a problem.

In order to form a covalent bond, the target needs to have a reactive site, usually a cysteine residue, but the drug needs to bind with the correct one. Biphasic binding can introduce selectivity, with the drug directed to this cysteine by first interacting with an adjacent pocket. It is then well positioned to form a covalent bond with the right cysteine. This mechanism combines the benefits of both selectivity, and long duration of action.

Where can covalent bonds be seen in practice?

The resurgence in interest was heralded by ibrutinib, a BTK inhibitor to treat blood cancers that was discovered at the biotech Celera in the early 2000s, developed by Pharmacyclics, and now marketed by AbbVie. A second covalent tyrosine kinase inhibitor, AstraZeneca’s osimertinib, joined it on the market in 2016. It targets EGFR, and is used to treat certain lung cancers. Both are highly effective, and very well tolerated.

These products prove covalent drugs don’t have to be beset by side-effect issues, and it is not inevitable that they will react indiscriminately. Many more covalent drugs are now in the development pipeline, countering the preconceptions of “what a drug has to look like.”

Tackling the ‘undruggable’

Covalent drugs also allow us to consider targets long thought undruggable. Top of the list is another cancer target, KRAS, a gene in which driver mutations are associated with about a fifth of all cancers. It has no obvious binding site for a traditional drug molecule. A common KRAS mutation that drives cancer replaces a glycine with a cysteine close to a shallow binding site.

Reacting this residue with a covalent drug can lock KRAS into an inactive conformation. The first drug to act in this way, Amgen’s sotorasib, reached the market for non-small cell lung cancer patients in 2021. Others are in the clinic.

Significant efforts are being made across the drug discovery community to understand which targets might have an accessible cysteine close to a potential active site. Assisting these efforts, the biophysics platform here at Sygnature is invaluable when looking for that biphasic binding effect, as it can give a clear mechanistic picture. We have also been looking at covalent fragments to probe binding activity.

The regulators have already signalled that they are happy to approve covalent drugs, as long as they pass all the normal safety and efficacy hurdles. With the amount of interest in the field, it feels like simply a matter of time before others reach the market, transforming the lives of patients.

Will you be a part of that wave? Get in touch with our experts today.