Scientists have devoted lots of time and money trying to find inhibitors of human Ras proteins. About 30% of cancers depend on mutated versions of Ras for growth and survival, making Ras mutants appealing cancer drug targets.
The fruits of these efforts have been molecules that bind Ras mutants only weakly or inhibit them indirectly by preventing the proteins from localizing in cell membranes, where Ras signaling occurs. But neither type of inhibitor has proven to be effective as an anticancer agent, and Ras has been deemed to be virtually “undruggable.” The problem is considered so important that NIH’s National Cancer Institute recently announced a $10 million-per-year initiative to fund research on therapies for cancers with Ras mutations.
Kevan M. Shokat of the University of California, San Francisco, and coworkers aren’t participants in that initiative, but an approach they developed has yielded the first inhibitors of mutant Ras with high potency for killing cancer cells (Nature 2013, DOI: 10.1038/nature12796).
Drug researchers Gideon E. Bollag and Chao Zhang of Plexxikon, a Berkeley, Calif., biotech company, comment in Nature that the approach is “perhaps the most promising strategy ever pursued toward developing an anticancer drug that targets mutant Ras proteins.” Araxes Pharma, a company Shokat cofounded, has an arrangement with Janssen Biotech to develop optimized versions of the inhibitors for clinical evaluation.
The inhibitors reach the heart of the beast by bonding covalently to a mutant amino acid in the Ras protein targeted in the study. This protein, K-Ras(G12C)—so called because it was discovered by someone whose name starts with K and its 12th amino acid, glycine, is replaced by cysteine—is strongly associated with lung cancer.
Shokat’s team screened for inhibitors by treating K-Ras(G12C) with “tethering compounds” that can inhibit proteins by forging covalent bonds with individual amino acids. Their crystal structure of a K-Ras(G12C)-inhibitor complex shows inhibitor-induced rearrangements of flexible protein components that stabilize an inactive Ras conformation, turning off Ras signaling. Covalent inhibitor bonding is a strong interaction that can aid potency, and in this case the inhibitors selectively bind the mutant protein over normal K-Ras. But reactive compounds can also bond with nontarget biomolecules, potentially causing side effects.
Ras researchers Fumi Shima and Tohru Kataoka of Kobe University Graduate School of Medicine, in Japan, tell C&EN that insufficient data on downstream signaling and a data discrepancy in the new study cast doubt on whether it conclusively demonstrates Ras-specific inhibition.
But another Ras specialist, Sharon Campbell of the University of North Carolina School of Medicine, notes that “if the compounds work as Shokat and coworkers hope, they could be a nice way to treat the subset of lung cancers driven by this mutation.”