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

Abstract

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 Y884 SOS1 and A73 KRAS 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 KRAS G13D 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.

Breaking Oncogene Addiction: Getting RTK/RAS-Mutated Cancers off the SOS

“…Bayer Pharmaceuticals first reported the development of a specific SOS1 inhibitor, BAY-293, that was suitable for in vitro experiments but not in vivo use . In this issue, Ramharter et al describe the discovery of BI-3406, a potent, orally available SOS1 inhibitor . BI-3406 showed exquisite specificity, inhibiting the protein–protein interaction (PPI) between SOS1 at Y884 and KRAS on R73; intriguingly, small substitutions the chemical backbone converted BI-3406 from an inhibitor to an activator, showing how marginal substitutions can dramatically change protein–protein interactions.…”

“…In contrast, KRASG13D mutated proteins have a relatively weak interaction with NF1, allowing NF1 to inactivate wild-type HRAS and NRAS in the absence of EGFR stimulation and making wild-type RAS signaling EGFR-dependent in these cells. In the current study, Ramharter et al show that BI-3406 strongly synergizes with the second-generation EGFR-TKI afatinib to inhibit the growth of KRAS G13D -mutated cells both in situ and in xenograft studies . These data suggest that vertical inhibition of proximal RTK signaling using an RTK inhibitor in combination with an inhibitor of proximal RTK signaling may be a common therapeutic strategy to enhance RTK inhibitor efficacy and treat cancers dependent on RTK signaling.…”

The Role of Wild-Type RAS in Oncogenic RAS Transformation

“…SHP2 and SOS1 are common proximal RTK signaling intermediates; the development of potent, specific inhibitors for both SHP2 (SHP099 [ 131 , 132 ]; RMC-4550 [ 133 ]) and SOS1 (BAY-293 [ 134 ]; BI-3406 [ 135 , 136 ]) has led to new approaches to treating RAS -mutated cancers. Both SHP2 [ 131 , 132 , 133 ] and SOS1 [ 134 , 135 , 136 ] inhibitors are effective in inhibiting cell growth in situ as single agents in cells with RTK/RAS pathway mutations that are dependent upon RAS nucleotide cycling, including cells with EGFR mutations, KRAS (G12/13) mutations, LOF NF1 mutations, and BRAF type III mutations, but not in cells with KRAS Q61 mutations, BRAF Type I/II mutations, or concomitant PIK3CA mutations. In xenograft studies using adult lung, pancreas, or colon cancer cell lines, SHP2 inhibitors enhanced the efficacy of covalent KRAS G12C inhibitors [ 18 , 114 ] and both SHP2 [ 113 , 137 ] and SOS1 [ 135 ] inhibitors enhanced the efficacy of MEK inhibitors.…”

Turning the Actin Nucleating Compound Miuraenamide into Nucleation Inhibitors

“…Interestingly, it has very recently been shown in a different kind of protein–protein interaction (PPI) that the exchange of just one atom can be enough to revert an SOS1 activator into an SOS1 inhibitor. 12 …”

“…Thus, intriguingly, it is possible to tune not only the potency but also the mode of action of derivatives of miuraenamide, making this natural compound an interesting scaffold for further studies. Interestingly, it has very recently been shown in a different kind of protein–protein interaction (PPI) that the exchange of just one atom can be enough to revert an SOS1 activator into an SOS1 inhibitor …”