Abstract 7008: Development of a potent SOS1 degrader exhibiting superior combination effects with anti-cancer drugs in various tumor models

Abstract Background: Son of Sevenless 1 (SOS1) is a crucial guanine exchange factor (GEF) for KRAS, facilitating the activation of RAS family proteins by promoting the exchange of GDP for GTP at its catalytic site. It also binds GTP-bound KRAS at an allosteric site, enhancing its GEF activity through positive feedback. Loss or genetic inactivation of SOS1's GEF function reduces the survival of tumor cells with KRAS mutations. 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. Results: UBX-144 demonstrated superior degradation activity, achieving sub-nanomolar DC50 levels in the NCI-H358 NSCLC (non-small cell lung cancer) cell line and in transiently transfected SOS1 mutant cells, where it effectively degraded SOS1. A time-course degradation assay demonstrated half-maximal degradation of SOS1 within 2 hours of treatment. A mechanism of action (MOA) study revealed that UBX-144 degrades SOS1 via the ubiquitination-proteasome system, mediated by CRBN E3 ligase. Both UBX-144 and UBX-164 inhibited cell proliferation across various cancer types, including gastric, colon, breast, lung, brain cancers, and chronic myeloid leukemia (CML). A combination synergy study showed that UBX-204 synergized with various inhibitors in NCI-H358 and MIA-PaCa-2 cell lines. In vivo pharmacodynamic (PD) data showed that UBX-144 effectively degraded SOS1 protein in tumors in a U87-MG xenograft model. Experiments using the glioblastoma cell line derived xenograft model demonstrated a compelling in vivo profile, with 10 mg/kg administration of UBX-144 resulting in significant tumor growth inhibition (TGI: 101%) and maximal degradation values exceeding 95% in tumors. Conclusion: We have successfully discovered novel SOS1 degraders exhibiting remarkable anti-tumor activities. In particular, the superior anti-cancer effects of combination treatments with other drugs were confirmed across various cancer cell lines, highlighting its potential as an excellent combination partner. We demonstrate that SOS1 degraders provide a promising therapeutic option for RTK/RAS/MAPK-dependent cancer patients. Citation Format: Jiyoung Kim, Ji Youn Park, Yeajin Woo, Soohyun Lee, Beomseon Suh, Han Wool Kim, So Hyuk Kim, Yongdae Kwon, Heejung Moon, Yeeun Kim, Jungmin Ahn, Jihye Lee, Je Ho Ryu, Song Hee Lee. Development of a potent SOS1 degrader exhibiting superior combination effects with anti-cancer drugs in various tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7008.