AI Article Synopsis
- KRAS is a key oncogenic driver in cancers and relies on protein-protein interactions (PPIs) for its signaling, especially with SOS1 for activation.
- A study found that adding just one atom between specific residues in SOS1 can turn the SOS1 activators into inhibitors.
- This new method, which utilizes small modifications rather than large molecules, shows promise in inhibiting challenging PPIs like SOS1-KRAS, especially when combined with the EGFR inhibitor afatinib to target KRAS mutant colorectal tumors.
Article 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 and A73 is sufficient to convert SOS1 activators into SOS1 inhibitors. We also disclose the discovery of . Combination with the upstream EGFR inhibitor afatinib shows efficacy against KRAS mutant colorectal tumor cells, demonstrating the utility of 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.
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| http://dx.doi.org/10.1021/acs.jmedchem.0c01949 | DOI Listing |
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