Abstract C020: Discovery of novel SMARCA2 degraders with synergistic activity against SMARCA4 and KRAS co-mutant tumors

Abstract Emerging therapeutic modalities such as PROTACs and other bifunctional molecules are transforming the landscape of early stage therapeutic discovery programs. SMARCA4 and other subunits of the SWI/SNF chromatin remodeling complex are frequently mutated in non-small cell lung cancer with a frequency of up to 33% in advanced stage disease, making it the most frequently mutated complex in lung cancer. SMARCA2 is synthetic lethal to SMARCA4, and a high value therapeutic target. Interestingly, SMARCA4 has also emerged as a predictor of poor response to various therapies, including immunotherapy and KRAS inhibitors. Here, we report the discovery of novel SMARCA2 degrading small molecules with synergistic antitumor activity against SMARCA4 and KRAS co-mutant tumors. Specifically, we describe the identification and characterization of YDR1 and YD54, two potent, selective and orally bioavailable Cereblon-based SMARCA2 PROTACs. Biochemically, YDR1 and YD54 degrade SMARCA2 with DC50 of 7.7nM and 3.5nM respectively in SMARCA4 mutant lung cancer cells. Functionally, these compounds selectively inhibited growth of SMARCA4 mutant cancer cells and and modulate the YAP signaling pathway for therapeutic benefit. Further, we showed anti-tumor growth inhibitory activity of YDR1 and YD54 in SMARCA4 mutant xenograft models of lung cancer. Finally, we show that YDR1 and YD54 synergize with the KRAS G12C inhibitor sotorasib to inhibit growth of SMARCA4 and KRAS G12C co-mutant lung cancer cells. These findings provide compeling evidence for the future development SMARCA2 PROTACs, either as single agent or in combination with standard of care, against SMARCA4 mutant cancers. Citation Format: Yonathan Lissanu, Sasi Kumar Kotagiri, Nicholas Blazanin, Yanyan Han, Xiaobing Liang, Yawen Wang. Discovery of novel SMARCA2 degraders with synergistic activity against SMARCA4 and KRAS co-mutant tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C021.