Chibuike Okafor: How Amgen Defeated the ‘Undruggable’ KRAS
“For 40 years, KRAS was a mystery no one could solve, a challenge that crushed even the best scientists. It was the key driver of many cancers, yet completely untouchable. Drug companies tried and failed so many times that they finally called it “undruggable.” It wasn’t just difficult—it was nearly impossible.
The reason? KRAS was too smooth, too fast, with no obvious weak spots. Most drugs work by competing with natural molecules that bind to a protein, but KRAS had GTP clinging to it with an insane strength—about 10 picomolar (pM). To compare, most strong drugs bind in the nanomolar (nM) range, which is already impressive. But KRAS-GTP binding? 100,000 times stronger. Imagine trying to pry open a vault with a toothpick. That’s what scientists were up against.
Then came Amgen. Instead of competing with GTP, they looked at KRAS from a different angle. Deep in its structure, they found a tiny groove—but only in the KRAS G12C mutant, a form of KRAS linked to lung and colorectal cancer. That was the opening they needed. And that’s how they created sotorasib (Lumakras, AMG 510)—a drug that didn’t try to fight GTP but completely shut KRAS down. It locked KRAS into an inactive state, stopping the cancer in its tracks.
This was history in the making. Margaret Chu-Moyer and her Amgen team led the charge, proving that “undruggable” was just a challenge waiting for the right solution. When the FDA approved sotorasib, the entire cancer research world took notice. Scientists who once thought KRAS was hopeless now saw a new frontier. A wave of new research began—better KRAS inhibitors, combination treatments, and new hope for cancer patients.
For decades, KRAS stood undefeated. But science, persistence, and a fresh way of thinking proved that nothing is truly impossible. Amgen didn’t just break the rules—they rewrote them.”
Written by Chibuike Okafor
Research Assistant at Department of Pharmaceutical/Medicinal Chemistry University of Jos
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