The Undruggable Ras Oncoprotein

The small molecule ligand (red) binds to a unique site on the Ras oncoprotein (brown) and blocks the Ras activation by SOS1 (cyan). (c) Genentech

Dr. Guowei Fang and his colleagues at Genentech have discovered a potential new target for drug cancer therapies. He presented his research yesterday at the ASCB Annual Meeting in Denver, Colorado.

The target is a small molecule-binding pocket on Ras, the most commonly mutated oncogene in humans. The oncogene (a gene that can mutate to cause cancer) is found in approximately a quarter of all tumors, and is a marker for a poor prognosis.

“It had been considered to be undruggable,” said Dr. Fang, “because it’s a protein and it’s intracellular.”

Using nuclear magnetic resonance spectroscopy, Dr. Fang and his drug-discovery team sorted through 3,300 small molecule compounds and found 25 compounds that bind to Ras oncoproteins. All of the proteins bound to Ras in the same location, making it a promising target.

So far, because all of the compounds have such a low affinity for the protein, all of the research has been done in vitro. The next logical step in the effort to create a medicinal compound is to increase the affinity of the binding compounds.

Dr. Fang’s manuscript is currently under review, and the team hope to have it published soon.

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