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A new kind of drug will help fight previously untreatable conditions | New Scientist

I think we will look back at 2026 as a landmark in medicine, the year in which the first protac drug was approved. What’s special about protacs? Well, while most drugs simply block their targets, protacs utterly demolish them. Per molecule, protacs are far more potent, and they can also do things other drugs just can’t.

To put it in sporting terms, existing drugs tackle their opponents one-on-one, and sometimes that opponent evades them. Protacs are like a referee who red-cards an entire team, taking them off the field altogether – a game changer.

I first got excited about protacs in 2005 when I was a features editor at New Scientist, and promptly commissioned a piece about them. At that time, it was far from clear whether a brilliant idea could be turned into practical drugs, so it’s fantastic to see decades of hard work finally bearing fruit.

To understand why protacs are so revolutionary, we need to start with conventional drugs. Almost all the pills you pop – ibuprofen, say – contain drugs that consist of small molecules. The shape of these molecules allows them to bind to specific proteins, to block or stimulate them. For instance, ibuprofen binds to and inhibits enzymes that produce chemicals that promote inflammation.

Small-molecule drugs have some big advantages. They’re cheap to make, can get inside cells and can be taken as a pill because they can also pass through the gut lining and into the bloodstream. But their small size means they’re not that specific. They tend to bind to other molecules besides the one they are supposed to target and thus have undesirable side effects.

And in many cases, it simply isn’t possible to find a small molecule to block the activity of a protein. The issue is that each drug molecule can’t just bind to any part of a target protein. To have an effect, it must bind to the active site of the protein – the workface – but sometimes small parts of the active site don’t have a distinctive enough shape. Such proteins are referred to as undruggable.

That’s why many newer drugs consist of large molecules, most commonly proteins known antibodies. (Any drug whose name ends in “-ab” is an antibody.) The large size of antibodies means they can bind to targets with exquisite precision, making them highly effective and safer. To create them, you get immune cells to generate antibodies to the desired target and then pick the best one. It sounds easy, but it took many decades to perfect.

The downside of antibodies is that they are really expensive because they can be made only in living cells. Their large size also means they must be injected because they can’t get through the gut. Nor can they get into cells once they’re in the bloodstream. So, while antibodies could bind to many undruggable proteins, they can’t get into cells to reach them.

The other thing to mention is that both small-molecule drugs and antibodies must be in contact with the target to work – the one-on-one part I mentioned above. Protacs work differently. Essentially, they stick a “recycle me” label on a protein in a cell. That means just one protac molecule can label and get rid of tens or hundreds of molecules of that protein. And because they’re not blocking or stimulating the target protein, they don’t have to bind to the active site. Anywhere on the target will do, making many undruggable targets druggable.

Craig Crews and Raymond Deshaies came up with the idea for protacs when they met at a conference in 1998. They knew that cells have waste disposal factories, called proteasomes, that break down and recycle faulty or excess proteins. They also knew that the “recycle me” label on proteins consists of a short chain of ubiquitin molecules. Add this label to a disease-causing protein and the proteasome will destroy it.

But how? The “recycle me” labels are usually added to specific proteins by enzymes known as E3 ubiquitin ligases. Maybe it could be done by bringing an E3 ligase into close contact with the target protein by creating a molecule that binds to both, Crews and Deshaies speculated.

Within a few years, they had shown the answer was yes, it works. They called their creations proteolysis targeting chimeras, or protacs – the proteolysis bit of the name refers to the destruction of proteins, and the chimera bit to the fact that protacs are made by joining two parts that each bind to a different thing.

Moving outside the lab

The first protacs were an academic exercise, Crews told me in 2020. The molecules were so large they had to be injected into cells – a non-starter for a drug.

In 2008, Crews set out to create small-molecule protacs. This is a challenge because each protac must bind to two molecules – the target protein and an E3 ligase – whereas conventional small-molecule drugs need bind only to one. While he succeeded in making protacs small enough to behave like small molecules, they are still somewhat larger than conventional drugs. “I call them large small-molecules,” he told me last week.

By 2013, Crews was confident enough to found a company called Arvinas. For its first products, Arvinas played it safe. Rather than going for undruggable proteins, it targeted hormone receptors in cancer cells. For instance, the growth of some types of breast cancer is driven by receptors that respond to oestrogen. There are already several drugs that work by targeting these receptors, but resistance can develop.

One way that cancers become resistant is by making more receptors, until even the highest tolerable drug doses can’t block all the receptor molecules – the one-on-one problem. “Since we’re actively degrading the receptor, we don’t have that limitation,” Crews said in 2020. In trials, people with advanced breast cancer that had spread around the body survived more than twice as long when given the protac drug vepdegestrant, compared with those given a conventional drug. As a result, vepdegestrant was approved by the US Food and Drug Administration in May.

“The approval is a milestone for the field,” says Crews. There was already huge interest in the idea of targeted protein degradation, with around 100 companies working on it and around 80 trials under way, he says. The approval will boost this even further. Increasingly, companies are starting to target undruggable proteins, too.

All sorts of variations on protacs are also being explored. For instance, simply linking two proteins together with a protac-type molecule can be a powerful tool. Crews himself recently developed “riptacs”, or regulated induced proximity targeting chimeras. Riptacs link a protein abundant in cancer cells to a protein essential for cell survival, blocking the function of both and killing the malignant cells. Riptacs performed so well in an initial trial against prostate cancer that US pharmaceutical firm Johnson & Johnson acquired the technology.

Of course, protacs are far from the only game in town. There are now a bunch of approaches based on stopping proteins being made in the first place, including CRISPR gene editing and epigenetic editing. These techniques are very promising, too, but they have limitations. For instance, delivery is a major challenge because of the large molecules involved. Nor do they get rid of existing proteins, says Crews, which can be important. “We’ve been able to show that a protac can degrade half of a protein population [in a cell] within 2 hours.”

So, I’m hopeful we will be seeing all kinds of new treatment based on protacs, ultimately helping billions of us. The approval of vepdegestrant may have received barely a headline, but if it is indeed the first of many, we will look back at it as a major milestone.