Characterization of BTX-10908, a first-in-class, orally bioavailable SOS1 bifunctional degrader for the treatment of KRAS- and RTK-driven cancers.

e15192 Background: Despite early clinical responses of targeted therapeutics against specific nodes in the RTK-RAS-MAPK pathway, limitations in the depth and duration of efficacy occur due to the emergence of adaptive and acquired resistance mechanisms. Resistance can result from the removal of feedback inhibition to reactivate RTKs, on-target amplification and new mutations. The efficacy of these oncogene-targeted agents in the clinic could be improved by co-treatment with additional therapies that address either type of resistance mechanism. The RAS guanine nucleotide exchange factor, Son of Sevenless 1 (SOS1), represents an ideal target to enhance clinical potency of other pathway inhibitors for two reasons. In addition to mitigating inputs from upstream RTKs to downstream RAS proteins, SOS1’s activity is also regulated by ERK- and RSK-mediated negative feedback inhibition with upstream and downstream inhibitors alleviating this inhibition to reengage pathway activation. Methods: To address this need, we utilized our PRODEGY platform to generate orally bioavailable, Cereblon (CRBN)-based SOS1 bifunctional degrader, BTX-10908, for the treatment of KRAS- and RTK-driven tumors. Results: BTX-10908 demonstrated rapid and potent SOS1 degradation with <10nM DC 50 and maximum degradation > 90%. Consistent with BTX-10908’s mechanism of action, SOS1 degradation required CRBN and the proteasome. Not only did it reduce active RAS levels, but BTX-10908 also inhibited downstream signaling proteins (pERK, pRSK, pS6) and lowered ERK-mediated transcripts in KRAS- and EGFR-mutant as well as MET amplified cell lines under anchorage-independent (3D) conditions. Additionally, drug washout experiments demonstrated prolonged suppression of pERK and ERK-regulated transcripts with SOS1 degradation whereas rebound occurred quicker with SOS1 inhibitors. BTX-10908 displayed CRBN- and SOS1-dependent antiproliferative activity with IC 50 values ranging from 0.5-20nM. Notably, BTX-10908 was significantly more potent than the clinical SOS1 inhibitor at reducing pERK levels and cell viability in multiple KRAS- and RTK-driven cell lines. Oral administration of BTX-10908 resulted in dose-dependent SOS1 degradation and tumor growth inhibition in H358 (KRAS G12C) and H441 (KRAS G12V) xenografts. The combination of BTX-10908 with KRAS G12C inhibitors (Sotorasib, Adagrasib) and various RTK inhibitors (EGFR, Met, BCR-ABL, and FLT3) prevented pathway reactivation driven by these inhibitors resulting in synergistic effects in in vitro proliferation assays and enhanced tumor growth inhibition in KRAS-mutant xenograft models. Conclusions: Our developmental candidate, BTX-10908, displayed robust in vitro and in vivo activity supporting its further development for monotherapy and combination therapies of KRAS and RTK-driven cancers.