Shokat says the presence of this cysteine conveyed certain chemical properties that gave his team a unique handle for drug design. Cysteine is unique among the 20 natural amino acids in its ability to form covalent bonds. Most commonly bonds are made between two cysteines to stabilize protein structure, but if a free cysteine is present, as in G12C K-Ras, a specifically designed drug can form a bond to the cysteine.
"Everybody else (developing drug design strategies) had been thinking they had to go after all the Ras mutants," Shokat says. "We looked for what no else had done and we picked this particular mutation because of its chemical properties."
Over a three-year period, the team developed a preliminary screen with more than 500 chemical compounds to see if they could identify one that would bind covalently and "tether" with K-Ras G12C. Their studies led to the identification of a potent inhibitor of K-Ras. To get a better picture of how this compound interacted with K-Ras, the scientists solved crystal structures of the compound bound to K-Ras.
When they examined the data, Shokat and his team found a previously undescribed pocket on the surface of K-Ras near the cysteine residue. "This pocket is new," Shokat says. "No one had found it before."
Investigating further, they found that the compound interferes with Ras in such a way that it alters its natural affinity for its substrate GTP, but not GDP. "One of the most important aspects of this is that this small molecule inhibits only mutant K-Ras and not the normal protein," Shokat says.
Next steps include continuing to optimize this compound so that it can be further tested to see how well the compound kills cancer cells with the G12C mutation. Shokat said he and his colleagues have started a company called Araxes Pharma, LLC., which has entered into a partnership with Janssen Biotech, a division of Johnson & Johnson, to develop these
|Contact: Jim Keeley|
Howard Hughes Medical Institute