These Protein Picker-Uppers Keep Your Cells Clean and Healthy

This story is one of a series on how we cleanse–from organizing your house to washing your tuchus.

Of all the existential intergalactic threats ever faced by the crew of the starship Enterprise, perhaps none smolders more brightly in the minds of classic Star Trek followers than the gaping, antiproton-beam-backlit maw of the Planet Killer. What could be more memorable, after all, than a miles-long, barrel-shaped machine that prowls through room, inhaling planets through one extremity and chopping them into rubble to be expelled out the other? Now imagine a microscopic version of that and you’ve got yourself a proteasome, one of the most essential molecular machines inside the human body. Instead of broken off planets though, it hacks apart proteins.

This tubular apparatus of orderly extermination is basically a cellular garbage disposal, continuing thousands of damaged, misfolded, or otherwise obsolete proteins from piling up inside your cells like so much interplanetary space junk. Over the past two decades, as biochemists began figuring out how this natural trash-clearing system operates, some discovered ways to trick it into aborting nearly any protein they wanted.

Today, investors are running billions of dollars into what many hope will be the next generation of blockbuster medications based on programmable proteasomes. In the last few years, nearly every major pharmaceutical firm has begun negotiating deals with startups was engaged in targeted protein degradation–as the rapidly expanding drug strategy is known–or spinning up their own internal growing programs. Whereas tiny molecules like ibuprofen and benadryl gum up proteins, and Crispr knocks out the genes that attain proteins, protein degraders offer a radical new space to selectively reach into cells and onslaught a whole host of historically difficult-to-treat diseases brought about by misbehaving molecules, from Alzheimer’s to Parkinson’s to many types of cancer.

At least, theoretically. The key is getting a protein in the best interest labeled for dumping. That’s the job of a special enzyme called a ubiquitin ligase; anything it slaps a chemical tag on gets carried off to a proteasome and, poof , no more protein. Getting it to tag a specific protein is simply a matter of designing a molecule that can tether the ligase and the protein together. The idea’s been around since the late ’9 0s, but until recently, most shows had taken place only in academic laboratories. That’s because most pharmaceutical companies presupposed these proteasome-recruiting molecules, which are quite large and ungainly by drug criteria, would never be able to slip across the membranes of intestinal cells and get into the bloodstream. In other words, the biology operated, but the chemistry was no good.

But a small Connecticut-based biotech company called Arvinas is changing that premise. Founded in 2013 by Yale biochemist Craig Crews, one of the scientists who pioneered the now-patented protein disappearing act, Arvinas invested its first few years chemically tweaking its molecules to attain them work inside the human body. In March, it began recruiting patients for the first-ever clinical trial of protein degraders. The company will test out appropriate methods on prostate cancer patients first, with another experiment starting later this year for breast cancer. “The concept is incredibly compelling, but the big question has always been, can you get these large molecules to behave well? ” says Tim Shannon, development partners at Canaan Spouse and an early investor in Arvinas who provided as its CEO until 2015. “That’s what we’re about to find out. Because if you can create one of these successfully, then you can do more.”

The idea behind the company’s first candidate is that it degrades the androgen receptor, which grabs onto testosterone, a hormone that has been shown to fuel prostate cancer. Hormone therapies given to treat prostate cancer or is an impediment from coming back after surgery or chemo block those receptors, cutting off the render of testosterone to cancer cells and diminishing tumors. But after a while, these cells adapt, sometimes mutating their receptors or adding more to their surfaces so they can suck up every bit of testosterone available, basically evolving resist to the therapies. Same thing for some types of breast cancer, but in that case estrogen is the hormone that adds ga to the fire. Arvinas hopes that by disappearing the receptors to these hormones down the molecular doomsday machine rather than only blocking them, it can help people who’ve become resistant to existing hormone therapies.

Protein-degrading isn’t a cure-all, though. While most of these molecules has been demonstrated good specificity–they’re not out tagging innocent bystander-proteins–there’s currently no way to tailor their trash-flagging in different parts of the body. Just like small-molecule medications, protein-degraders will impact not just receptors in, say, tumors, but anywhere cells are displaying them, including in healthy tissues. For proteins that medicines have never been able to target before, the potential side effects are completely unknown. At least where androgen and estrogen receptors are concerned, researchers know what to expect.

And that’s more or less the main goal of these first human tests–to really just see if protein degraders work as expected in a well-understood system. Arvinas expects to have that data in hand by early next year. If successful, more experimental experiments include the following, though so far no one’s saying much about which illness they plan to treat. Last month, another startup called Kymera Therapeutics signed a $70 million, four-year agreement with Vertex Pharmaceuticals to accelerate the push to get its still-secret protein degraders into the clinic. Novartis is reported to have its own hush-hush nominee on track for a test later this year. And C4 Therapeutics, a small Boston biotech, signed a $415 million deal with Biogen in January to develop therapies for neurological diseases, but it has yet to disclose specifics. Arvinas has its own licensing agreement with Genentech, merit $650 million, to collaborate on additional treatments. They’re lining up to tame a host of alien proteins, to boldly go where no medication has gone before.


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