Abstract 6056: Identification of first-in-class, orally bioavailable SOS1 bifunctional degraders for the treatment of KRAS- and RTK-driven cancers

Abstract Monotherapies which target nodes within the RTK-RAS-MAPK pathway often display early potency in the clinic, but their preliminary response is limited as tumors begin to regrow due to adaptive and acquired resistance mechanisms. Disrupting proteins that mitigate either type of resistance mechanism in combination with oncogene-targeted agents could help extend and enhance the clinical potential of these drugs. Son of Sevenless 1 (SOS1), a RAS guanine nucleotide exchange factor, is a highly attractable protein to target given its role in transducing inputs from upstream receptor tyrosine kinases (RTKs) to downstream RAS proteins to regulate signaling pathways involved in cell proliferation and survival. Additionally, SOS1 is subject to MAPK-mediated negative feedback inhibition and drugs targeting upstream and downstream nodes relieves SOS1 from this inhibition resulting in pathway reactivation. To address this need, we have developed orally bioavailable SOS1 bifunctional degraders for cancers driven by KRAS and RTKs. Our top two lead molecules demonstrate CRBN- and proteasomal-mediated SOS1 degradation with DC50s 10nM and maximum degradation 90%. Consistent with this notion, SOS1 degradation inhibited downstream signaling marker phopshoERK with IC50s 5nM and were 26- or 53-fold more potent when compared to the clinical SOS1 inhibitor. Notably, the SOS1 degraders exhibited weaker SOS1 binding compared to other SOS1 inhibitors highlighting that the potency is heavily driven by the catalytic nature of degradation rather than occupancy-driven events. Both SOS1 degraders displayed CRBN- and SOS1-dependent antiproliferative activity in KRAS- and EGFR- mutant, solid tumor cell lines as well as in BCR-ABL driven, CML cells with IC50 values ranging from 0. 5-10nM. Consistent with our in vitro data, oral administration of our SOS1 degraders in mice harboring H358 (KRAS G12C) and H441 (KRAS G12V) xenografts resulted in SOS1 degradation, phosphoERK reduction and significant tumor growth inhibition. While SOS1 degrader monotherapy demonstrated in vitro and in vivo potency, combination of mutant or allele specific EGFR and KRAS inhibitors and ABL inhibitors with our proof-of-concept degraders prevented pathway reactivation associated with these inhibitors and lead to a more durable response. These combinations also yielded synergistic effects in in vitro proliferation assays as well as enhanced tumor growth inhibition in KRAS-mutant xenograft models. Together, our SOS1 degraders alone and in combination with other targeted agents demonstrated anti-tumor activity in a variety of KRAS- and RTK-driven cancer cell lines and xenograft models. These results support the potential of orally bioavailable SOS1 degraders to help mitigate pathway reactivation for enhanced efficacy and prolonged response duration. Citation Format: Kyle Begovich, Angela Schoolmeesters, Navin Rajapakse, Elena Martinez, Qiao Liu, Arvind Shakya, Akinori Okano, Venkat Mali, Shenlin Huang, Aparajita Chourasia, Leah Fung. Identification of first-in-class, orally bioavailable SOS1 bifunctional degraders for the treatment of KRAS- and RTK-driven cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6056.