One Atom Makes All the Difference: Getting a Foot in the Door between SOS1 and KRAS

KRAS,
the most common oncogenic driver in human cancers, is controlled
and signals primarily through protein–protein interactions
(PPIs). The interaction between KRAS and SOS1, crucial for the activation
of KRAS, is a typical, challenging PPI with a large contact surface
area and high affinity. Here, we report that the addition of only
one atom placed between Y884SOS1 and A73KRAS is sufficient to convert SOS1 activators into SOS1 inhibitors. We
also disclose the discovery of BI-3406. Combination with
the upstream EGFR inhibitor afatinib shows in vivo efficacy against KRASG13D mutant colorectal tumor cells,
demonstrating the utility of BI-3406 to probe SOS1 biology.
These findings challenge the dogma that large molecules are required
to disrupt challenging PPIs. Instead, a “foot in the door”
approach, whereby single atoms or small functional groups placed between
key PPI interactions, can lead to potent inhibitors even for challenging
PPIs such as SOS1-KRAS.