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May 16, 2013
 |  BC Innovations  |  Targets & Mechanisms

Raising the Ras inhibitor bar

About a year after U.S. researchers developed small molecule inhibitors of the intractable target wild-type Ras, a Japanese team has identified compounds that hit Ras mutant tumors in mice.1 The team now is trying to ramp up the potency of the mutant-targeting compounds and optimize the structures to make them more drug-like.

Ras family proteins play central roles in cell growth and proliferation. The proteins cycle between an inactivated, GDP-bound state (Ras-GDP) and an activated, GTP-bound state (Ras-GTP). Guanine nucleotide exchange factors such as son of sevenless homolog 1 (SOS1) facilitate Ras activation by promoting the release of GDP from inactivated Ras-thereby allowing intracellular GTP to bind and reactivate it-and by enhancing the activation of Ras after it binds GTP.

Of the three Ras isoforms, K-Ras is most frequently dysregulated in cancer, with activating mutations found in about 80% of pancreatic cancers, 40% of colon cancers and 25% of lung cancers. Collectively, mutations in all three isoforms-K-Ras, v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS) and neuroblastoma Ras viral oncogene (NRAS)-occur in about 20% of all cancers.

Nevertheless, Ras proteins had long been considered undruggable because they lack well-defined surface pockets suitable for binding drug molecules. In 2012, independent groups at Vanderbilt University School of Medicine and the Genentech Inc. unit of Roche used fragment-based drug discovery to identify small molecules that blocked...

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