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Abstract 6368: Discovery of potent, orally bioavailable, SOS1 inhibitors for KRAS-driven tumors


 KRAS is an oncogene implicated in a wide variety of tumors (~21% of solid tumors harbor KRAS mutations). KRAS interaction with Guanidine Exchange Factors (GEFs) is crucial for its activation, with SOS1 being the predominant GEF. SOS1 inhibition is thus expected to be an effective strategy for targeting the downstream signaling pathway, resulting in anti-proliferative activity in RAS-driven cancers. We have identified multiple potent and selective SOS1 inhibitors, demonstrating significant reduction of GEF activity in a dose-dependent manner. The lead compounds show anti-proliferative activity across a panel of WT and mutant KRAS cell lines, and are synergistic with MAPK pathway inhibitors including KRASG12C inhibitor Sotorasib. Correspondingly, significant reduction in PD biomarkers, pERK and pAKT is demonstrated in KRAS mutant cell lines. PK-PD correlation is also established in a tumor bearing mice model, with dose-dependent reduction of both pERK and pAKT. The lead compound shows good ADME properties, and is orally bioavailable, making it amenable for further in vivo profiling.
 Citation Format: Sanjita Sasmal, Sukanya Patra, Venkatesham Boorgu, Mahesh Yanamadra, Ashok Ettam, Nagaraju Dunaboyina, Githavani Kummari, Ram Mohan Yengala, Balakrishna Lakhavath, Jayita Das, Satheesh Sunkanapally, Pravalika Reddy, Megha Mariam Mathew. Discovery of potent, orally bioavailable, SOS1 inhibitors for KRAS-driven tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6368.