Seizing the moment that proteins are correctly aligned to hit previously undruggable targets.
CEO: Chris Varma, Ph.D.
Based: South San Francisco, California
Clinical focus: Triggering the degradation of undisclosed proteins that are major drivers of different cancers.
The scoop: Frontier Medicines is working to redefine the term “undruggable” when it comes to proteins that have frustrated researchers for years.
The easiest-to-reach therapeutic targets are proteins with firm, interwoven structures—the kind that provide numerous grooves and holes where a small molecule can bind and instantly block their function. But beyond those, as much as 90% of the body’s 20,000 or so proteins can be much less cooperative.
Frontier CEO Chris Varma, Ph.D., takes the more malleable chains of amino acids and compares them to pieces of string. Hold them up, and they hang down with no corners, no gaps and no places to stick a small-molecule drug. However, if you shake the string back and forth—as a protein would move in a living system—useful pockets and crevices begin to appear, if only momentarily.
“If you look at a class like transcription factors, they have a lot of what are called intrinsically disordered regions, which is what enables that kind of floppiness,” Varma says.
But being there at the right time—when those pockets form—and attaching the right molecule means you can lock down that protein and hold it in place. So it’s not that drugging them is impossible. It just hasn’t happened yet.
What makes Frontier fierce: By using chemoproteomic techniques to screen large numbers of targets within an active cellular environment—and combining them with a protein database, licensed from UC Berkeley, that contains more than 100,000 novel hot spots and pockets—Frontier hopes to develop at least three internal clinical programs, starting in cancer.
And to capture these chaotically transient binding sites, which may exist for only a split second, the company aims to use covalent chemistry for a stronger and snappier molecular bond.
But sometimes that’s not enough on its own. Of the 40-plus protein targets Varma’s team has been interrogating, only about half have responded effectively to the addition of a new passenger.
“The other half of the time, the protein doesn't care,” Varma says. “So even if you found that pocket and stuck a covalent molecule in there, it may not even affect its function. Those cases, in particular, were the motivation to develop our protein degrader technology—because if we couldn't inhibit it, we at least wanted to degrade the target. We can now bind about 90% of human proteins. … So the degrader part is actually much more straightforward.”
A veteran of startup biotechs, Varma previously helped establish Blueprint Medicines, a member of the 2011 Fierce 15 class, and Warp Drive Bio. The former focuses on targeted oncology therapies and recently showed that its RET inhibitor could shrink tumors in difficult-to-treat lung cancer. Warp Drive, meanwhile, initially sought out novel targets, before its tie-up with Revolution Medicines last year.
“For these small companies—while it's really hard to go after these well-validated and credible targets—that is something that a small company can actually do, if it's got the right technology,” Varma says.
With Frontier, Varma hopes its technology will allow it to advance quickly through the hit-to-lead stage of drug development. The company can establish whether a ligand will work on one of its previously undruggable proteins within the first 30 days of a project, he says.
“After that it's very standard small molecule chemistry, something the industry has been doing for 100 years,” he added. “We already have those answers on our first one or two projects, and we will have the answers on the rest of them soon.”
In June, Frontier picked up $67 million in its series A round to fuel its work, with backing from Deerfield Management, Droia Oncology Ventures and Varma’s previous employer, MPM Capital. That money will go toward pipeline development and building out the company’s staff, which grew by 50% this summer alone, including the hiring of three biopharma veterans in key leadership positions.
AstraZeneca’s VP of oncology research, Kevin Webster, Ph.D., joined as chief scientific officer, while Johnson & Johnson’s Johannes Hermann, Ph.D., took on the chief technology officer role. Frontier also brought on Arvinas’ former chief scientific officer, Jim Winkler, Ph.D., to head up its protein degrader technologies.
Hermann helmed the machine learning efforts at J&J’s Janssen division before leading the data science unit for its medical devices and technology arm. At Frontier, he will help integrate computational approaches into the chemoproteomics and drug development platform.
Overall, Varma hopes to see the company’s total staff count reach the mid-20s before the end of the year, to help fill out its new 38,000-square-foot home in South San Francisco’s biotech hub at Oyster Point.
“We’re shooting big,” Varma says.
Investors: Deerfield Management, Droia Oncology Ventures, MPM Capital, DVCV Bio and RA Capital Management