March 13, 2014

A new way to target cancer-driver Ras

Vanderbilt researchers have discovered small molecules that turn off cancerous Ras signals in a new way.

Aberrant activation of Ras – a signaling protein that regulates cell growth and survival – plays a role in up to one-third of all human cancers. Turning off activated Ras is a promising therapeutic strategy, but Ras has been a challenging target because it lacks suitable binding “pockets.”

Stephen Fesik, Ph.D., Orrin H. Ingram, II Professor of Cancer Research, and colleagues now report an alternate approach: targeting proteins that regulate Ras, instead of Ras itself. They report in the March 4 Proceedings of the National Academy of Sciences the identification of small molecules that activate the Ras regulator, SOS (Son of Sevenless). SOS catalyzes the exchange of guanine nucleotides (GTP for GDP) on Ras, which is a required step for Ras activation. The newly identified small molecules bind to a unique pocket in the Ras:SOS:Ras complex. They increase the rate of guanine nucleotide exchange in vitro, but paradoxically disrupt downstream Ras signaling.

The compounds provide novel tools for studying acute Ras activation and represent a new approach for inhibiting Ras signaling.

This research was supported by grants from the National Institutes of Health (OD006933, CA095103, GM007347), from the Lustgarten Foundation and by the Ann Melly Scholarship in Oncology.

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