March 28, 2019

Cancer’s SOS

Stephen Fesik and colleagues are advancing cancer drug discovery with the characterization of small molecules that modulate RAS, an important target for anti-cancer therapies.

by Sanjay Mishra

RAS proteins regulate growth, survival and proliferation of cells in their active state. However, the uncontrolled activation of RAS causes approximately a third of all tumors and helps cancerous cells evade anti-cancer drugs. Thus RAS is an important target for effective anti-cancer treatments.

RAS proteins become “active” through the exchange of guanine nucleotides (GTP for GDP), which is catalyzed by guanine nucleotide exchange factor proteins such as Son of Sevenless homologue 1 (SOS1).

Stephen Fesik, PhD, and colleagues previously discovered small molecules that bind to SOS1 and activate nucleotide exchange on RAS.

Now, in the journal ACS Chemical Biologythey report that these compounds modulate two downstream signaling pathways via independent cellular responses. They also identify a potent SOS1 agonist that rapidly elicits on-target molecular effects at substantially lower concentrations than those causing off-target effects.

The discovery, they concluded, will allow them to further define the on-target utility of SOS1 agonists and to advance their drug-discovery efforts.

This research was supported in part by the Lustgarten Foundation and the National Cancer Institute (grant CA095103).