Case Study: How the XtalPi Team Discovered a Selective, Novel Lead Series for Key Cancer Target SMARCA2

Loss-of-function mutations in SMARCA4 occur in various cancers, leading to an increased dependency on the structurally similar SMARCA2 for activity. This makes SMARCA2 an attractive therapeutic target due to its increased importance in cancer cell survival.

However, identifying novel small-molecule SMARCA2-selective inhibitors poses significant challenges. To address this, XtalPi leveraged its advanced AI-powered discovery platform and Cryo-EM technology, opening up new possibilities for targeted cancer treatments.

Our Key Results: 

• Discovered a novel lead series with high efficacy and 20-fold selectivity for SMARCA2 over SMARCA4 in biochemical assays, showcasing strong potential for further development.
• Identified a unique SMARCA2 binding pocket using Cryo-EM at 2.9 Å resolution, offering new insights for the design of selective inhibitors and advancing structure-based drug discovery.
• Achieved 100% library compound synthetic success rate by proprietary synthetic feasibility prediction models.