Small Molecules Can Directly Inhibit RAS

Activating RAS mutations are among the most common genetic events in human cancers, but no effective RAS-targeted therapy currently exists. RAS proteins have been thought to be undruggable due to their lack of well-defined surface pockets amenable to small-molecule binding, but recently reported crystal structures of RAS proteins in complex with a nonhydrolyzable GTP analogue suggested that such pockets may exist as RAS cycles between GTP-bound active and GDP-bound inactive states. Based on this structural information, Shima and colleagues performed an in silico screen of over 40,000 compounds to identify small molecules predicted to dock into GTP-bound RAS surface pockets. Of 97 candidates evaluated in vitro, 1 inhibited binding of GTP-bound MRAS and HRAS proteins to the effector protein CRAF1 with micromolar potency, and a second compound with comparable activity was identified by a computer-assisted similarity search of additional compounds. Neither compound inhibited CRAF1 kinase activity in vitro, but nuclear magnetic resonance spectroscopy suggested that they instead bound a hydrophobic surface pocket on RAS near effector- binding interfaces that could competitively inhibit CRAF1 binding and prevent its activation by RAS. Consistent with this model, both compounds reduced phosphorylation of multiple effectors downstream of RAS and RAF, including MAP-ERK kinase (MEK) and ERK, and inhibited anchorage-independent growth and proliferation of HRAS-mutant NIH3T3 cells. The compounds also inhibited anchorage-independent growth of cancer cell lines harboring HRAS, KRAS, or NRAS mutations, but had little activity against RAS-wild-type cancer cells. Notably, daily oral administration of the compounds appeared to be well tolerated and led to 50% growth inhibition of a KRAS-mutant colorectal cancer cell line in vivo in association with reduced ERK phosphorylation and increased apoptosis. Deriving more potent, specific inhibitors from these lead compounds may ultimately allow direct targeting of RAS in multiple cancers and render RAS druggable.

Shima F, Yoshikawa Y, Ye M, Araki M, Matsumoto S, Liao J, et al. In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras–effector interaction. Proc Natl Acad Sci U S A 2013 Apr 29 [Epub ahead of print].

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