BAY-293 (BAY293) is a novel, potent, cell-active small-molecule SOS1 inhibitor with anticancer activity. It functions by preventing RAS activation by interfering with the RAS-SOS1 interaction, with an IC50 of 21 nM. Using a KRASG12C–SOS1cat NMR fragment-based screening assay, BAY-293 was discovered, and it effectively interferes with the interaction of KRAS and its exchange factor SOS1. Since the late 1980s, it has been known that significant oncogenes with a high frequency of occurrence in human cancers are mutations in the RAS genes. Due to these mutations, the small GTPase RAS is less able to hydrolyze GTP, which maintains this molecular switch in a constitutively active GTP-bound form that uncontrollably triggers oncogenic downstream signaling. Guanine nucleotide exchange factors, which enable RAS to cycle from the inactive GDP-bound state to the active GTP-bound form, are one tactic to lower the levels of active RAS. Using the crystal structures of KRASG12C-SOS1, SOS1, and SOS2, the binding sites, mechanism of action, and selectivity were determined. These inhibitors inhibit the reloading of KRAS with GTP, which results in antiproliferative activity, by preventing the formation of the KRAS-SOS1 complex. With an IC50 of 21 nM, compound 23 (BAY-293) is the last one to selectively inhibit the KRAS-SOS1 interaction. It is a useful chemical probe for further studies.

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.