Discovery of potent SOS1 inhibitors and their pharmacological investigations to disrupt the RAS-SOS1 interaction

Mutants of RAS are major oncogenes and are prevalent in many human cancers, however efforts to develop drugs that directly inhibit the corresponding constitutively active RAS proteins have been unsuccessful so far, although there are promising new findings for KRas-G12C covalent inhibitors. We focused on SOS1, the guanine nucleotide exchange factor (GEF), and an activator of RAS. We identified good starting points for medicinal chemistry activities using both high-throughput and fragment screens. Initial optimizations resulted in the discovery of the first nanomolar SOS1 inhibitors, which effectively downregulated active RAS in tumour cells. Here, the key findings on our path to identifying novel potent and cellular active small molecule inhibitors will be described. These inhibitors efficiently disrupted 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 the reloading of KRAS with GTP and, therefore, showed antiproliferative activity. Our probe BAY-293 selectively inhibited the KRAS–SOS1 interaction with an IC50 of 21 nM and is a valuable chemical probe for further investigations. In cells with wild-type KRAS the complete inhibition of the RAS–RAF–MEK–ERK pathway was observed. In a mutant KRAS cell line, SOS1 inhibition resulted in a reduction of pERK activity by 50%. Together, the data indicate that inhibition of GEFs may represent a new viable approach for targeting RAS-driven tumours.