Biotechnology startup Arvinas is developing proteolysis-targeting chimeras (PROTAC) that combat cancer by degrading disease-causing proteins. The company's first PROTACs will target prostate and breast cancers, and a recent deal with Pfizer will allow Arvinas to develop PROTACs for other cancer types.
Taking an entirely different approach to fighting cancer, biotechnology start-up Arvinas (New Haven, CT) has spent the past 5 years developing proteolysis-targeting chimeras (PROTAC). The technology is based on a simple concept: Proteasomes break down proteins that have been tagged with ubiquitin by E3 ubiquitin ligases, so tagging oncogenic proteins for degradation will potentially stop their oncogenic signal.
Recently, Arvinas teamed up with Pfizer in a discovery-based deal worth up to $830 million, while continuing to develop other promising PROTACs in its internal pipeline.
Craig Crews, PhD, founder and chief scientific advisor of Arvinas, started working on PROTAC technology at New Haven's Yale University during the early 2000s. “I wanted to hijack the cell's own quality-control machinery that normally turns over proteins to degrade disease-causing rogue proteins that we want eliminated,” he explains.
To do this, his lab developed dumbbell-shaped PROTACs: One end of the molecule binds to a target protein and the other binds to an E3 ubiquitin ligase. The ligase tags the target protein with ubiquitin, signaling to the cell's proteasomes that the protein should be destroyed.
“We're dragging proteins to these E3 ligases that normally wouldn't be recognized by them, saying ‘I want this one tagged because I know this one is causing a problem,’” Crews says, adding that, unlike an inhibitor that must stay bound to a protein to work, a PROTAC needs only to temporarily bridge the target protein and E3 ligase.
“It's constantly recruiting these disease-causing proteins to the E3 ligase for tagging, and so there is a multiple turnover catalytic quality to this,” Crews explains. “Just a little bit of drug can get in there and wipe out all the preexisting population of this disease-causing protein.”
Thomas Kodadek, PhD, of Scripps Research Institute in Jupiter, Florida, who is not involved in Arvinas, predicts that “PROTACs are likely to make vastly improved versions of some existing [cancer] drugs. But where they could really change things fundamentally is in the future where people are trying to drug some of these so-called undruggable targets.”
To advance their work, Arvinas signed deals of upward of $400 million each with Merck and Genentech in 2015, and expanded the Genentech deal late last year. In its most recent deal, Arvinas will develop PROTACs for new protein targets identified by Pfizer that the pharmaceutical company will move through clinical trials.
Arvinas's internally developed estrogen-receptor PROTAC for breast cancer and androgen-receptor PROTAC for prostate cancer are also progressing: In 2017, the company selected its first clinical trial candidates for each disease. Arvinas presented preclinical results at the 2017 San Antonio Breast Cancer Symposium demonstrating the ability of its PROTAC to degrade estrogen receptor and inhibit tumor growth. Similarly, they showed compelling evidence of effectiveness for the androgen-receptor PROTAC at the 2018 Genitourinary Cancers Symposium, held February 8–10 in San Francisco, CA.
John Houston, PhD, president and CEO of Arvinas, says he expects that clinical trials for the androgen-receptor PROTAC will begin before the end of this year, and for the estrogen-receptor PROTAC in 2019.
“There are a number of big pharma companies that are moving into this space and looking at protein degradation, and even smaller companies that have started up behind us,” he says. “It's quite a competitive space right now, which is exciting, but it means we've got to keep moving fast to stay in the lead.” –Catherine Caruso
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