Abstact

Son of Sevenless Homologue 1 (SOS1) is a promising oncology target with inhibitors in phase 1/2 clinical studies. A focused HTS triage led to a singular SOS1 series having a pyridyl core. The conformational preference of the diamide pyridyl core was critical to binding potency, leading to pyrazine and pyridyl being the preferred motifs. Application of structure-based design to build into a buried lipophilic pocket led to a significant 50-fold potency enhancement. Strategic fluorination of aryl rings and substituents generated compounds with favorable dipoles, low P-gp and BCRP efflux, and high rat Kp(u,u). Multiple analogues were progressed into in vivo PK/PD studies where they were combined with a KRAS(G12C) inhibitor. Combination treated tumors in mice showed deeper, more sustained reductions in DUSP6 mRNA and phosphorylated ERK compared to KRAS(G12C) inhibitor alone. Thus, these novel CNS penetrant SOS1 inhibitors have potential to enhance antitumor responses when combined with RAS or MAPK inhibitors.