For Bayer's kRas lead generation program we applied a broad range of biophysical and assay techniques to advance a hit cluster from a fragment to a cellular active lead candidate.
For Bayer's kRas lead generation program, we identified potent and cell-active small-molecule inhibitors which efficiently disrupt the interaction between KRAS and its exchange factor SOS1.
This mode of action was confirmed by a series of biophysical techniques. The binding sites, mode of action, and selectivity were elucidated using crystal structures of KRASG12C–SOS1, SOS1, and SOS2. By preventing formation of the KRAS–SOS1 complex, these inhibitors block reloading of KRAS with GTP, leading to antiproliferative activity. The final compound 23 (BAY-293) selectively inhibits the KRAS–SOS1 interaction with an IC50 of 21 nM and is a valuable chemical probe for future investigations.