Idea Behind Warp Drive’s New Cancer Attack Was Hiding In Plain Sight

Xconomy Boston — 

[Corrected, 11/12/15, 4:17pm. See below.] The way pharmaceuticals work is often described as keys fitting locks. A drug goes into the body and finds its target because it matches up with a small stretch of biological material within cells or on their surface.

But there are all kinds of biological doors which have no locks—no place for a key to fit—and behind those doors lie the answers to many diseases, researchers believe.

The scientists behind Cambridge, MA-based Warp Drive Bio say they have found a way to open some of those doors—in particular, a way to match drugs with a family of genes called RAS implicated in more than 30 percent of all cancers.

Finding drugs that attack RAS-driven cancers is a daunting and urgent task, highlighted by the fact that the U.S. government’s National Cancer Institute two years ago launched a special initiative to build tools, such as new cell lines and experimental mice, to help frustrated RAS researchers.

Warp Drive founder and chief scientific officer Greg Verdine was on the RAS initiative’s advisory board. He and his Warp Drive colleagues unveiled this past weekend what they say is new drug-hunting technology and insights to go after RAS and other so-called “undruggable targets.”

“It’s a national priority to drug RAS, and I think we’ve cracked that problem,” he says.

That remains to be seen. Warp Drive launched with fanfare nearly four years ago but has been quiet about its science since then. However, Verdine in that time has climbed into then out of the CEO seat, leaving his tenured Harvard University professorship for a full-time gig at the company.

If all goes well, says Verdine, the company could have anti-RAS cancer drugs in human testing by the end of 2018.

Why do Verdine and colleagues say they have found keys for locks that no one else could find? Let’s step back a bit. Traditional small-molecule drugs, synthesized from chemicals, need to find notches or cavities to latch onto their targets. Without a place to grab—or “bind,” in drug chemistry parlance—small molecules can’t do their work, which would either be to block some bad biological effect or promote a good one.

But what if a small molecule can latch onto something else, and that something else is able to bind to otherwise slippery surfaces? Verdine and company say they have found that something else—and the answer to the RAS riddle—hiding in plain sight.

In every single cell in the body—and therefore in cancer cells, too—there is an abundant protein called FKBP. Turns out, it’s very good at binding to proteins, such as those expressed by the RAS gene family, that don’t afford small molecules much purchase. “You need the big surface of the FKBP protein to bind with the flat surface of the target,” says CEO Laurence Reid (pictured above).

Warp Drive got to FKBP because its scientists followed the trail laid down by two old drugs, rapamycin (Sirolimus) and FK506. Both are derived from soil bacteria. (“Rapa,” because the bacterium in that case came from Easter Island, or Rapa Nui. FK506 was discovered in Japan; it’s also known as fujimycin and tacrolimus.)

And both do something extremely unusual. Whether they’re attacking fungi in soil or treating people for various diseases, the compounds hit their targets only with the help of FKBP, which isn’t just present in every cell in the body, it’s present in a wide swath of Earth’s organisms, from yeast to humans. [A previous version of this paragraph held an inaccurate biological definition.]

Once rapamycin or FK506 joins forces with FKBP—which stands for FK506 binding protein—the larger structure has enough area to bind to their target’s elusive flat surface.

The drugs have been prescribed for years to lower the risk of organ transplant rejection and for other uses. Both have been studied and developed as much perhaps as any pharmaceutical compounds in the world, including investigations in cancer and anti-aging. The earliest work nearly three decades ago at Boston’s Vertex Pharmaceuticals (NASDAQ: VRTX) revolved around teasing out the structures of these interactions to come up with a less toxic version of FK506, as chronicled in Barry Werth’s The Billion Dollar Molecule.

In 2003, Vertex cofounder and Harvard chemist Stuart Schreiber wrote a tome in Chemical & Engineering News about more than a decade of work—his and others’—based on the use of small molecules to explore biology, and in particular “the ability of small molecules to bind two proteins simultaneously,” which is what rapamycin and FK506 do. Schreiber and colleagues discovered FKBP12, the form of the FKBP protein relevant to human therapeutics, in the late 1980s.

All this deep history makes Warp Drive’s light-bulb moment all the more puzzling. No one else ever thought of this?

“People knew that rapamycin and FK506 were cooperating with FKBP, but no one suspected you could broadly reprogram FKBP. If nature did it twice, it probably could do it many more times,” says Verdine.

“Conceptually, it’s not a novel idea that a protein-small molecule complex can be a potent inhibitor of a specific target,” says Matt Kaeberlein, a University of Washington biologist who has studied rapamycin extensively as part of his longevity research. Kaeberlein says that the leap forward would come more with the design of “a system to hit specific targets for which there aren’t already good inhibitors or activators. If they can do that, it would be impressive.”

The key here is Verdine’s phrase “broadly reprogram FKBP.” With technology it calls small molecule assisted receptor targeting, or SMART, Warp Drive says it can use FKBP as a skeleton key to fit many locks, potentially. What it needs is a guide—a small molecule that enters a cell, finds FKBP, and bound together, the new complex then targets the offending protein, such as RAS. FKBP stays the same; it’s the small molecule that is customized to match the target.

The cooperative mechanism has been known for a long time. But “a lot of what we know about the structures and the exact role of FKBP12 is more recent,” says Brian Kennedy, CEO of the Buck Institute for Research on Aging in Novato, CA, whose research focuses in large part on rapamycin and its target. The growing body of knowledge could be one reason Warp Drive feels it has made a breakthrough.

The concept has some similarities to the revolutionary gene editing tool CRISPR-Cas9. The gene-cutting scissors (the Cas9 enzyme) stay the same, but the ribonucleic acid guide that joins with the scissors and tells them where to cut can be swapped out rapidly.

One big difference, however, is that customizing the small molecule that binds to FKBP and the disease target is no easy feat. “We’re learning to do that drug discovery exercise for the first time, it’s much more complex than a simple lock and key,” says Verdine. “We’re dealing with the modality of two proteins coming together with the small molecule in the ‘glue’ between them.”

He and CEO Reid, who joined earlier this year from Alnylam Pharmaceuticals, are confident that Warp Drive scientists have the requisite skills. They are in the midst of “hardcore drug hunting” to find the right small molecules for four different genetic scenarios, all various forms of RAS, Verdine says.

Warp Drive has not yet tested anything in animals. To hit its goal of human trials before 2019, the company will need to answer several questions, Kennedy says. He notes that rapamycin is quite big for a small molecule, too big typically to get into cells, but nature has perfected it over millions of years. Creating new versions that preserve the ability to bind to FKBP, but also hone in on new targets like RAS, might require going smaller, too.

Another question from Kennedy is whether FKBP12 is flexible enough to “mediate the interaction” between the new small molecules Warp Drive designs and RAS or other disease targets.

Warp Drive CEO Reid says the company already understands the FKBP interaction “with multiple surfaces and forms of RAS. We believe that many intractable targets will be accessible with our SMART modality.”

Another question is resistance. RAS has never been drugged. Who’s to say that, even when a key fits the lock, RAS-driven tumors won’t simply mutate—change their locks—as so many other tumors are able to do?

Here is Reid’s answer: “FKBP is present at very high levels inside the cell. We know that significant reductions in FKBP levels are tolerated by the cell. We thus believe that FKBP is an unlikely source of resistance mutation. More generally, we intend to develop multiple RAS antagonists that are collectively designed to inhibit RAS chronically and maximize our chance of successful long term inhibition.”

Warp Drive launched in 2012, backed by Boston venture group Third Rock Ventures, Greylock Partners, and international drug firm Sanofi. Officials then described what they called a “genomic search engine” to sift through the world’s microbes for molecules that would hit difficult-to-reach drug targets. In the past, products sleuthed from nature were the core of the drug business. Think old products like aspirin, derived from willow bark, or even fairly new ones, like the diabetes treatment exenatide, gleaned from Gila monster saliva.

The search engine—Reid prefers the term “mining platform”—helped hone in on the FK-related biology. Warp Drive will also use it to look for new antibiotics and other drugs, Reid says. But the matter at hand is now to design drugs that can attack RAS-driven cancers. “It’s certainly an important target,” says the Buck Institute’s Kennedy, “and it’s certainly a creative approach. We’ve struck out trying to find small molecules for RAS. We need creative approaches.”