BAY-293

BAY-293 is a pan-KRASi compound impairing interaction of the GTP-loading SOS1 with KRAS at the low nanomolar level (IC50 = 21 nM), where SOS1 is the guanine nucleotide exchange factor (GEF) and activator of RAS. BAY-293 inhibits the activation of RAS in HeLa cells, with IC50 values in the submicromolar range, and shows efficient antiproliferative activity against wild-type KRAS cell lines (K-562, MOLM-13) and cell lines with KRASG12C mutation (NCI-H358, Calu-1), with IC50s between 1000 to 3500 nM. This compound, moreover, efficiently inhibits pERK levels in K-562 cells after incubation for an hour, having no effect on the total protein levels of ERK. What it is rather interesting is that SOS1 inhibition shows a synergistic antiproliferative potential when combined with direct covalent KRASG12C inhibitors (i.e., combined with ARS-853 in a KRASG12C-mutated cancer cell line). Of particular note are also the extensive structural studies have been carried out to elucidate the mode of action/binding of BAY-293 and also for a number of its derivatives. BAY-293 is a valuable chemical probe for further investigation of RAS–SOS1 biology in vitro, but it is not optimised for in vivo studies.