Monophthalates of betulinic acid and related pentacyclic triterpenes inhibit efficiently the SOS-mediated nucleotide exchange and impact PI3K/AKT signaling in oncogenic K-RAS4B proteins.

Betulinic acid and other herbal pentacyclic triterpenes have attracted interest in cancer research as these natural products induce apoptosis and suppress tumor progression. However, the molecular basis of the antitumor effect is still unknown. Here we show that monophthalates of betulinic acid and related triterpenes inhibit GDP/GTP exchange in oncogenic K-RAS4B proteins the PI3K/AKT downstream cascade. According to a binding model based on molecular modelling, these derivatives act like a molecular glue that stabilizes an unproductive K-RAS4B:SOS complex. This represents a new mode of action and could be an attractive route for targeting RAS-related cancers.