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...