Abstract 5175: Discovery and characterization of once in a month intravenous and orally bioavailable SMARCA2 degraders for treating SMARCA4 mutant cancers

Key Points

• The aim is to discover and characterize SMARCA2 degraders as therapeutic targets for SMARCA4 mutant cancers.
• Utilized rational design to create SMARCA2 degraders.
• Applied ternary complex modeling algorithm, ALMOND, for design prioritization.
• Synthesized selected compounds and evaluated them in cellular assays.
• Conducted preclinical testing in SMARCA4 mutant xenograft models.
• Identified multiple potent and selective SMARCA2 degraders.
• Lead compound showed robust anti-tumor efficacy in various xenograft models.
• Developed long-acting IV formulation allowing administration once every four weeks.
• Achieved favorable oral bioavailability in multiple species.