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.”
