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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• KRAS is a key oncogenic driver in many human cancers, regulated by protein-protein interactions (PPIs).
• The KRAS-SOS1 interaction is essential for KRAS activation but presents a challenging target due to its large interface and high affinity.

Purpose of the Study:

• To investigate a novel strategy for inhibiting challenging PPIs, specifically the KRAS-SOS1 interaction.
• To discover and characterize a new inhibitor targeting the KRAS-SOS1 pathway.

Main Methods:

• Computational and medicinal chemistry approaches to design small modifications at the KRAS-SOS1 interface.
• Synthesis and biological evaluation of the novel inhibitor BI-3406.
• In vivo efficacy studies in xenograft models of KRAS G13D mutant colorectal cancer, often in combination with EGFR inhibitors.

Main Results:

• The strategic addition of a single atom between KRAS and SOS1 successfully converted activators into inhibitors.
• Discovery of BI-3406, a potent inhibitor of the KRAS-SOS1 interaction.
• BI-3406 demonstrated in vivo efficacy against KRAS G13D mutant colorectal tumors when combined with afatinib.

Conclusions:

• A "foot in the door" approach with minimal modifications can effectively inhibit challenging PPIs like KRAS-SOS1.
• BI-3406 represents a valuable tool for exploring SOS1 biology and offers a potential therapeutic strategy for KRAS-driven cancers.
• This work challenges the necessity of large molecules for disrupting difficult PPIs.