Big Pharma Bets on Body’s Garbage-Disposal System to Beat Cancer

New drugs called “degraders” could take disease-causing proteins out with the trash.

Craig Crews pioneered protein degrader drug technology.
Craig Crews pioneered protein degrader drug technology.

At their most basic level, many of the deadliest diseases are caused by nests of misguided proteins. Most medicines work by attaching themselves to these proteins and temporarily shutting them down. In the 1990s, Yale University scientist Craig Crews and a colleague had a radical idea: What if a drug could destroy a bad protein by making it a target of the body’s own molecular trash disposal machines?

For years, the idea remained a lab curiosity. Biotech investors wouldn’t initially back a company based on the concept, which Crews and a few other academics labored to prove could be a practical way to make drugs. The field got a big boost earlier this decade when scientists started discovering that some of the most successful medicines turned out to work by piggybacking onto these human trash collectors. Now it’s become one of the hottest new technologies for making pills. Crews and a biotech he founded, Arvinas Inc., are racing some of the world’s biggest pharmaceutical and biotech companies—Novartis, Amgen, and Gilead Sciences—to turn protein-degrading compounds into drugs. “By hijacking natural quality-control machinery inside cells, we are literally making problem proteins go away,” Crews says.

The new drugs, dubbed protein degraders, could be one of the most significant advances in drugmaking technology in decades. Unlike specialized gene therapies, treatments based on protein degraders could be mass-produced in pill form. There could be a range of applications, from vanquishing drug-resistant tumors to clearing clusters of disease-causing proteins from the brains of Parkinson’s or Alzheimer’s sufferers. “No other technology has the potential to have such a broad impact,” says Nello Mainolfi, founder and president of Kymera Therapeutics, a biotech that attracted $70 million in funding in May from Vertex Pharmaceuticals Inc. to use protein degraders to tackle undisclosed specialty diseases.

Crews struggled for years to attract investors.
Crews struggled for years to attract investors.

What’s perhaps most intriguing to drug scientists is that degraders could help researchers target thousands of proteins now considered “undruggable,” including several linked to common cancers. “This set of technologies is rapidly advancing,” says Robert Bradway, chief executive officer of drug giant Amgen Inc. “It will enable us to reconceive the druggable genome.” In May, Amgen spent $167 million to acquire Danish biotech company Nuevolution AB for its screening technology that will help it hunt for protein degraders.

The first targeted degrader drugs are just beginning human trials, so scientists won’t know how well they work in people for several years, and the potential side effects remain largely unknown. At least three cancer treatments based on degrader technology have reached human testing, including two Arvinas drugs, and more are expected in the next year or so. In June, Germany’s Bayer AG signed a pact worth more than $110 million with Arvinas to develop protein degraders for treating diseases, as well as agricultural applications including weed and insect control. The first drug produced by Kymera, which breaks down a protein linked to certain lymphomas, could begin human trials next year.

The human body’s disposal system breaks down old, unwanted, or damaged proteins into parts that later can be recycled into new proteins. A group of enzymes recognizes unneeded proteins and attaches molecular tags that mark them for destruction. Cylindrical structures inside cells called proteasomes then come along and cut the unwanted proteins up into pieces. When the process goes wrong, with key proteins recycled at an excessive or insufficient rate, certain deadly diseases can develop, such as cystic fibrosis, cervical cancer, or kidney cancer. Drugs that block the proteasomes behind the recycling, including Takeda Pharmaceutical Co.’s Velcade, are already available to treat multiple myeloma, whose fast-growing cells turn out to be very sensitive to the buildup of waste proteins. Only recently did scientists show that it would be practical to make drugs that do the opposite—use protein degraders to speed up the destruction of disease-causing proteins.

When Crews first started pursuing the concept in the late 1990s, he was working on understanding the mechanism of an experimental cancer drug that turned out to block the cell’s garbage disposal system. At a conference in Blaine, Wash., he met Raymond Deshaies, who was studying the same system at the California Institute of Technology. Over beers, they came up with the idea of developing drugs to activate the process to get rid of unwanted proteins.

The idea was to devise a Tinkertoy-like molecule with one end that sticks to a problem protein. The other end would attach to one of the body’s garbage disposal enzymes. This would tag the protein for destruction. But scientists didn’t know much about how to latch onto the enzymes that marked proteins for destruction with small chemicals. Crews’s colleagues were skeptical that the idea had practical applications. Crews worked for years to improve the technology. In 2013 he founded Arvinas, which has offices less than a mile from his lab at Yale.

By that time, others in the industry had unpacked some of the world’s most powerful drugs and found that degrading proteins played a role in their success. In 2010, Japanese researchers showed that thalidomide—a drug used to treat both leprosy complications and multiple myeloma cancer—bound to a key protein involved in degradation and limb development, which helped to explain how it causes birth defects. Then, in 2014, other scientists showed that multiple myeloma drug Revlimid, a successor to thalidomide that’s been a best-seller for Celgene Corp., induced the degradation of proteins that myeloma cells apparently use for growth. “That is when the field went on steroids,” says Deshaies, now senior vice president for global research at Amgen.

Another turning point came in 2015, when researchers from several teams working independently, including Crews’s lab and scientists from Dana-Farber Cancer Institute in Boston, showed that small chemicals that could potentially be packaged into pills could connect known cancer-causing proteins to the body’s disposal system for grinding up.

Novartis AG now has 60 to 100 scientists at any given time working on degraders, says James Bradner, who was on the Dana-Farber team and has been head of Novartis’s research arm since 2016. So far they’ve been able to degrade more than 50 proteins in the lab, leading to a half-dozen drugs in early testing. The first of them, for an undisclosed cancer target, just began human trials, Bradner says.

In New Haven, Arvinas has taken a more conservative approach. It’s working first on improving existing categories of commercial drugs, before moving toward untried or hard-to-hit targets. Its lead drug is being tested in advanced prostate cancer patients who have stopped responding to existing hormone treatments. The first safety results are due later this year.

A decade from now, a third of new drug approvals could be degraders, says Nathanael Gray, a chemical biologist working on degraders at Dana-Farber who is also a co-founder and scientific adviser of biotech C4 Therapeutics. The company has a deal with Biogen Inc. to pursue degraders for brain diseases. Says Gray: “There is really no disease that can’t be impacted by this technology.”

Source: Bloomberg

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