LGW16-03

LGW16-03 is an orally bioavailable, small molecule inhibitor of Son of Sevenless homolog 1 (SOS1), developed by Novartis for the treatment of advanced solid tumors harboring KRAS mutations. SOS1 acts as a guanine nucleotide exchange factor (GEF) that facilitates the transition of RAS proteins from an inactive GDP-bound state to an active GTP-bound state. By binding to the catalytic domain of SOS1, LGW16-03 disrupts the SOS1-RAS interaction, thereby inhibiting the activation of various KRAS mutants (pan-KRAS inhibition) and downstream MAPK signaling. This mechanism is particularly relevant for overcoming adaptive resistance or enhancing the efficacy of direct KRAS inhibitors, such as G12C-selective agents.