Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Mutations in RAS genes are prevalent oncogenes in human cancers.
• Active RAS drives unchecked oncogenic signaling by preventing GTP hydrolysis.
• Targeting guanine nucleotide exchange factors is a strategy to reduce active RAS levels.

Purpose of the Study:

• To identify small-molecule inhibitors targeting the KRAS-SOS1 interaction.
• To elucidate the binding sites, mode of action, and selectivity of these inhibitors.
• To evaluate the antiproliferative activity of identified compounds.

Main Methods:

• Biophysical techniques to confirm the mode of action.
• Crystal structures of KRAS-SOS1, SOS1, and SOS2 to determine binding sites.
• In vitro assays to assess inhibitor potency and selectivity.

Main Results:

• Identification of potent and cell-active small-molecule inhibitors of the KRAS-SOS1 interaction.
• Elucidation of binding sites and mode of action using structural biology.
• Compound 23 (BAY-293) selectively inhibits KRAS-SOS1 with an IC50 of 21 nM.

Conclusions:

• Inhibitors effectively block KRAS-SOS1 complex formation, preventing GTP reloading.
• This leads to reduced oncogenic downstream signaling and antiproliferative activity.
• Compound 23 serves as a valuable chemical probe for further cancer research.