Healthy Attachments

Healthy Attachments

The science practiced in Science Park is mostly hidden from view. But a promising new tactic in the fight against cancer is about to emerge from behind the doors of one Winchester Avenue lab.

Founded in 2013, venture capital-backed biopharmaceutical startup Arvinas is at the cutting edge of what Randy Teel, vice president of corporate development, calls “a hot area of research.” It’s known to scientists as protein degradation, and new drugs from Arvinas using this concept are about to enter the first phase of clinical trials at Yale New Haven Hospital and other sites nationwide.

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Arvinas’s research grew out of the Yale lab of Craig Crews, a professor of biology and chemistry. “I wanted to kind of change the way we do drug development,” Crews says. So, in 2001, his lab’s team of chemists and biologists stepped back from the conventional approach to attacking disease-causing proteins and tried something new.

Most protein-attacking drugs have relied on attaching themselves to what Teel describes as a “cleft” in the protein molecule—a space into which they can wedge themselves and “gum up the works” so the protein can’t do its damage. But there’s a problem with that model, Crews explains. “hese drugs are reversible. They fall off, and so… you need to have a lot of drug around.” He wondered: What if, instead of just binding a drug to “rogue disease-causing proteins,” we could get rid of those proteins altogether?

But how? The answer Crews’s lab landed on was already there, in the human body, via a mechanism that “tags” damaged proteins with a smaller protein called ubiquitin, thus marking them for disposal. The tagged proteins are then recognized by a proteasome—a protein complex whose job it is to break down the tagged proteins into amino acids. Crews’s lab set out to create a molecule that would harness that existing system in order to degrade harmful proteins.

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It was simply “an academic exercise” at first, Crews says. “But my lab is a combination of chemists and biologists working together, and therefore we were able to take this academic idea a little bit further.” What they ultimately created is what Crews describes as a “dumbbell-shaped drug.” Both ends are connectors: one to latch onto the “bad” protein, and one to latch onto an E3 ubiquitin ligase—part of the tagging mechanism—with a link in the middle. This drug—named PROTAC, for proteolysis-targeting chimera—briefly connects the protein with the ligase, causing it to be tagged for disposal. The body takes care of the rest. (For a helpful visual explanation, watch this video.)

Unlike conventional protein-attacking drugs, once a PROTAC releases one protein, it can go looking for another one. In its lifetime, each PROTAC appears to be able to handle the job up to 200 times, Teel says. “You can then use a whole lot less of the drug… which is great because you always want to give the patient as little drug as possible.” The PROTACs have other advantages as well. Unlike conventional drugs, they don’t need to bind tightly to a protein, and they can make their connection almost anywhere on the protein.

So, what does all this mean for human patients? That remains to be seen, but clinical trials begin early this year for some patients with mCRPC, a form of prostate cancer, at Yale New Haven Hospital and three other sites in Tennessee, Massachusetts and Nevada. Before midsummer, some patients with metastatic ER+ breast cancer will also enter clinical trials using PROTAC. It’s an unusual one-two punch for a young biopharmaceutical company, Teel says.

Patients in the trials will have already tried at least one therapy without success, perhaps a drug their body has become resistant to. Their next line of defense would often be chemotherapy, Teel says, an approach that makes a broad attack on the body rather than a targeted one. Those whose doctors help them enroll in the clinical trial will take one pill per day, keep up frequent checkups and undergo blood draws so researchers can track how the drug is behaving in the body and doctors can keep tabs on their health. In this first stage of the trials, Teel says, the goal isn’t to learn how well the drug might work. Instead, researchers will focus on its safety and “tolerability.” “There’s some really important information for us to learn before we ever get to talking about, ‘Is the drug efficacious?’” Teel says. If all goes well, a second clinical stage will follow, its timeline and goals driven by what happens now.

In the meantime, Arvinas is moving forward with its next projects, setting its sights on neurodegenerative diseases like Alzheimer’s and Parkinson’s as well as “undruggables,” proteins to which no small molecule is known to be able to bind. With investor dollars coming in above projections (after going public in September, the young company raised $120 million), Arvinas is also building its platform, more than doubling its work force in the past year.

A 24-year resident of New Haven, Craig Crews is thrilled to have Arvinas close to home and to his lab. The first company he started back in 2003, which produces a drug to treat multiple myeloma, is now based in San Francisco. This time, he kept things local, turning down an investment offer that would have required the company to set up shop in a big city.

The decision to stay in New Haven has paid off not only for Crews but for the company as a whole. As some pharmaceutical and biotech groups are leaving Connecticut, Teel says, “We are excitedly snapping up great talent from around the state.”

Another constituency that benefits: Crews’s students. While serving as Arvinas’s chief scientific advisor and continuing to run his own lab, the man Teel calls the “undisputed leader” in the field of protein degradation is still in the classroom at Yale. He’s teaching undergraduates a course in applied science that “brings to life” the chemistry and biology classes they’ve already taken and teaches them how to bring a scientific product to market.

After all, as specialized as the science might be, it’s got to mean something for regular people.

395 Winchester Ave, New Haven (map)
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Written by Kathy Leonard Czepiel. Image 1, of Randy Teel and associate scientist Brian Wysolmerski, photographed by Kathy Leonard Czepiel. Images 2-4—featuring pipette tips, the contents of a tissue culture hood and compound vials, respectively—taken by Stephanie Anestis Photography for Arvinas.

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