Volume 91 Issue 47 | p. 7 | News of The Week
Issue Date: November 25, 2013

Cancer Protein Meets Its Match

Drug Discovery: Researchers find first potent inhibitors of cancer-associated Ras protein
Department: Science & Technology
News Channels: Biological SCENE
Keywords: Ras, cancer, lung cancer, protein inhibitor, drug discovery
[+]Enlarge
In this crystal structure of the K-Ras(G12C)-inhibitor active site, the Ras protein surface is gray, a covalently linked inhibitor is at left, bound guanosine diphosphate is at right, the inhibitor-linked cysteine is yellow, and the protein’s metal ion is green.
Credit: Courtesy of Kevan Shokat
Image of a crystal structure of a mutated Ras protein with covalently linked inhibitor (left), bound guanosine diphosphate (right), inhibitor-linked cysteine (yellow), and metal ion (green).
 
In this crystal structure of the K-Ras(G12C)-inhibitor active site, the Ras protein surface is gray, a covalently linked inhibitor is at left, bound guanosine diphosphate is at right, the inhibitor-linked cysteine is yellow, and the protein’s metal ion is green.
Credit: Courtesy of Kevan Shokat

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.

[+]Enlarge
This molecule with an acrylamide terminus was the best inhibitor of a mutant Ras protein associated with lung cancer.
Structure of K-Ras(G12C).
 
This molecule with an acrylamide terminus was the best inhibitor of a mutant Ras protein associated with lung cancer.

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.”

 
Chemical & Engineering News
ISSN 0009-2347
Copyright © American Chemical Society
Comments
Ken Westover (Tue Nov 26 14:09:32 EST 2013)
Please note that a complimentary concept for directly targeting K-Ras G12C with small molecule inhibitors was published the same day as the Shokat article here:
http://onlinelibrary.wiley.com/doi/10.1002/anie.201307387/abstract

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