Nearly ten years ago, academics at Stanford University trying to divine how proteins fold into their complicated shapes—an action that can take a millionth to a thousandth of a second—began recruiting people at home to volunteer their computers in the off hours. Back then, crowdsourced computing muscle was necessary to probe the mystery of a basic biological function.
But a group of scientists and entrepreneurs believe that computers and various biotechnologies have since advanced enough to unlock an even deeper mystery: How proteins, instead of folding into a permanent shape, shimmy from one shape to another, and how those back-and-forth states can be exploited to treat disease. They’ve formed a startup called Relay Therapeutics to test the concept and make drugs for cancer and other diseases.
“Many of the motions that take place in proteins in the body are happening on the millisecond timescale,” says Mark Murcko, Relay’s chief scientific officer and cofounder. “We’d like to see and understand the nature of those motions.”
The investigation of protein motion, also known as protein dynamics, has been around for decades. Murcko (pictured) and interim CEO Alexis Borisy, who is also a partner at Relay’s main investor Third Rock Ventures, demur when asked if they’ve licensed a particular breakthrough technology from academia. “We’re taking advantage of cutting edge technology across many disciplines,” says Murcko, but “shiny toys” are “less important than having smart people work together.” Relay, which is based in Cambridge, MA, has 25 employees and hopes to grow to 40 next year.
One advantage Murcko and Borisy say they have are supercomputers, nicknamed “Anton” and designed by D.E. Shaw Research, specifically to explore molecular biology. When the firm showed off Anton in 2010 for its protein-folding prowess, founder David Shaw told the journal Nature that simulating one small protein for a millisecond took the computer about 100 days. (Shaw is a Relay cofounder, as are Matthew Jacobson of the University of California, San Francisco and Dorothee Kern of Brandeis University.)
Six years on, Murcko and Borisy say the time is right to turn understanding of protein motion into drug discovery programs. It’s not just the computing power that will help Relay make drugs, they say; there are now advances in other laboratory technologies. X-ray crystallography, which helps reveal the structure of proteins, can now be used to work in different temperature ranges. And nuclear magnetic resonance spectroscopy, which reveals a molecule’s physical and chemical structure, can record the interaction of a chemical drug and a moving protein.
But the computing connection is obviously important. D.E. Shaw is a Relay investor and is dedicating computing resources to the effort. (Borisy and Murcko declined to say how much.) Third Rock and D.E. Shaw have committed $57 million to the company in a Series A round.
Relay wants to make drugs that attach to proteins in unconventional spots. Proteins have sites where they bind to other substances and spark an activity. Many drug makers aim their drugs at these “active sites” to block the disease-causing activity. Protease inhibitors to treat HIV infection work this way, blocking an enzyme that the virus uses to spread.
But Relay wants to hit spots on a protein that are not active. There are several reasons to hit these so-called “allosteric” sites. For example, many proteins have cousins with similar features, and a drug sent to hit the active site could end up hitting the family members, as well, and cause side effects. Hitting a non-active site might also trigger beneficial changes in the protein. (Drug companies have pursued allosteric targets for years, with varying levels of success.)
Murcko was the chief technology officer at Vertex Pharmaceuticals (NASDAQ: VRTX) for two decades. Vertex was a pioneer in the use of X-ray crystallography to learn the structure of molecules that play a role in disease in order to aim drugs at them. (Vertex’s protease inhibitors to treat HIV and hepatitis C were the result of structure-based drug design.)
If that was the art of taking a snapshot of a protein, Relay wants to master the art of making movies. Very short movies—tens of milliseconds long. Borisy points out that scientists had theorized in the mid-20th century that protein dynamics were important, even before the first protein snapshot—of the blood molecule hemoglobin—was created. (This page has an animation of hemoglobin in motion, shifting from state to state as it binds to oxygen, courtesy of the Protein Data Bank.)
Murcko won’t say how long it might take for Relay to turn its insights into drug programs. But he says the firm plans to keep ownership of any cancer drugs it develops, while partnering with other companies who want to use Relay’s platform in other disease areas.
Photo of an IGFR protein with an allosteric inhibitor courtesy of Enzymologic via a Creative Commons license.
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