Folding Forum

After 40 years of effort, researchers have finally succeeded in switching off one of the most common cancer-causing genetic mutations in the human body. The finding promises to improve treatment for thousands of patients with lung and colorectal cancer, and may point the way to a new generation of drugs for cancers that resist treatment.
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The search for drugs to block previously discovered cancer-causing mutations was always straightforward: Researchers had to find a molecule that attached to the mutated protein and could stop it from functioning. That strategy worked for so-called kinase inhibitors, which also block a protein created by gene mutations. There are 50 approved kinase inhibitors on the market now. KRAS was different. The gene directs production of a protein that normally flexes and relaxes thousands of times a second, as if it is panting. In one position, the protein signals cells to grow; in the other, it stops the growth. With the KRAS mutation, the protein remains mostly in an “on” position, and cells are constantly forced to grow.

The standard solution would be a drug that would hold the mutated protein in the “off” position. But that seemed impossible. The protein is large and globular, and it doesn’t have deep pockets or clefts on its surface where a drug could slip in. It was like trying to drive a wedge into a ball of solid ice. “Our medicinal chemists referred to it as the Death Star,” said Dr. David Reese, executive vice president for research and development at Amgen. “It was so smooth.”

So Shokat and his colleagues began looking for a molecule that could do the trick. Five years later, after screening 500 molecules, they found one and discovered why it worked.

Their drug held the protein steady, making a crevice visible on its surface. “We never saw that pocket before,” Shokat said. The protein normally flexes and relaxes so quickly that the narrow groove had almost been impossible to see.

JimF wrote:Sounds familiar somehow.