Abstract
RAS-driven cancers represent a significant challenge in oncology, necessitating targeted therapeutics
that can effectively suppress aberrant signalling while minimizing off-target effects. Here, I present a novel SOS1 inhibitor FDB-AZHN-2025, designed using three innovative algorithms: Configuration Cloning, Manual Rotor Lock with Substituent Replacement and Strategic Functionalization Mechanism, and Structural Peptidomimetic Engineering. This inhibitor Exhibits high-affinity binding to TYR884 and ASP887 in Cdc25 homology domain of SOS1, characterized by an extended residence time, leading to sustained suppression of SOS1 catalytic activity. This interaction disrupts precise
positioning of SOS1’s helical hairpin motif, which normally displaces the switch 1 region of RAS, preventing the formation of essential salt bridges and hydrogen bonds between SOS1 and RAS , locking the conformational changes required for Mg² displacement and GDP release , Stabilizing SOS1 in an inactive conformation that cannot catalyse nucleotide exchange, the inhibitor prevents SOS1 from converting inactive RAS-GDP to active RAS-GTP. This effectively blocks the activation of downstream effector proteins in the MAPK pathway, including RAF, MEK, and ERK. The resulting suppression of RAS-dependent signalling impairs cellular proliferation and survival mechanisms that
drive tumour growth.