Vitals
Current affiliation: Revolution Medicines
Age: 36
PhD alma mater: Stanford University
If I were an element, I’d be: “Nitrogen. Many medicines depend on the placement and type of nitrogen atoms in a molecule, which can dramatically change how a drug interacts with its biological target.”
When I’m not doing chemistry, I enjoy: “Ice hockey, running, traveling, hiking, and following sports—particularly the Buffalo Bills and Buffalo Sabres.”
The cancer-causing protein KRas was once considered undruggable. KRas is compact, lacks the deep crevices that drugs might bind to, and mutates frequently. But that’s exactly the kind of interesting challenge that Revolution Medicines chemist Jim Cregg enjoys.
Cregg joined the firm—usually abbreviated as RevMed—in 2017, fresh off a PhD from Stanford University, where he had studied total synthesis in Barry Trost’s lab. A year later, RevMed acquired Warp Drive Bio, which had been developing small molecules that could bind a protein-folding chaperone with a smooth drug target; KRas was the perfect example of such a target. Though Cregg was just a junior scientist, he was put on the team marrying those two programs.
Right away, the team made some interesting discoveries. The scientists figured out how to make molecules that covalently target KRas G12C(ON), a tricky mutant form of the protein, and enabled them to be taken as pills instead of injections. That “was a huge hurdle for us,” Cregg says. They then discovered that their molecules could form a stable, noncovalent tri-complex that could stop multiple RAS mutants from sending signals to activate tumor-driving molecular pathways.
That tri-complex underpins RevMed’s lead drug candidate daraxonrasib—considered one of the most promising potential treatments for metastatic pancreatic cancer, nearly doubling survival time in a recent Phase 3 study—and elironrasib, which targets solid tumors, including non-small-cell lung cancer. And it has positioned RevMed as a leader in the field of KRas-driven cancers. If approved, daraxonrasib could make the firm around $7.6 billion, Leerink Partners analysts estimated in a research report last year.
Much of RevMed’s pipeline is owed to Cregg. He is the lead author on the papers describing the discoveries of daraxonrasib and elironrasib. “At RevMed, with the tri-complex technology, it’s new. There’s no playbook written about it,” he says. “I was excited to try new opportunities, really eager to take risks or take on a role that was probably above me, in all honesty.”
Now that those two drug candidates are in clinical trials, Cregg is back at the bench working on early-stage discovery and hoping to address what he calls “holy grail” targets that have long dogged chemists, just as KRas once did.
“Jim’s a very data-driven, detailed-oriented individual who is able to absorb an enormous amount of structure-activity relationship and structural changes, let alone the synthetic repertoire that you need to be able to make these very large and complex molecules,” says Adrian Gill, Cregg’s boss and RevMed’s executive vice president of discovery chemistry and head of early discovery. “He pretty much became our corporate memory.”
Cregg didn’t set out to be a medicinal chemist. He was on a premed track when he started as an undergraduate at the University of Pittsburgh. But a required organic chemistry class clicked everything into place for him. “It made more sense to me than a foreign language,” he says.
Cregg’s first brush with the biopharmaceutical industry was a summer internship at Pfizer, where he worked on cardiovascular drugs, the year before he graduated. But Cregg elected to do a PhD in his newfound love—organic chemistry—before making the leap to industry.
“He was a first-rate student,” Trost says. The two worked together on reaction methodology with an emphasis on total synthesis of complex molecules. Perhaps more importantly, Cregg emerged as a natural leader in Stanford’s chemistry program, mentoring undergrads. “The students appreciated him and his ardor for the science,” Trost says. Toward the end of his PhD, Cregg hiked the John Muir Trail—“just to do it,” he says—completing the 340 km trek in about 12 days.
“I like the experience of pushing,” Cregg says. “If I have a focus on something, like chemistry or these projects, I like to do it to the nth degree.”
Cregg may not be a bench scientist forever. He was promoted to director in 2023 and is eyeing leadership opportunities. Lucky for him, he’s already got a ringing endorsement from his boss. “Longer term, I could imagine myself working for Jim rather than the other way around,” Gill says. “He’s got that much talent.”
