Focused Multiparameter Optimization to Convert Potent Allosteric SHP2 Inhibitors into Brain-Penetrant Candidates

About this poster

SHP2 is a validated regulator of the RAS-MAPK pathway in oncology, yet no SHP2 inhibitor is approved and no active clinical trial currently addresses brain cancers, where poor CNS exposure continues to constrain therapeutic outcomes. This poster presents IRBM’s focused multiparameter optimization (MPO) strategy, integrating structure-based design, in silico property prediction, and iterative in vitro/in vivo ADME profiling, which converted potent, peripherally restricted inhibitors into the brain-penetrant candidate I-1000233 while preserving cellular activity. The work provides a practical framework for enabling CNS exposure in small molecules, with relevance for primary brain tumors and metastatic disease. Download the poster to explore the SAR, design strategy, and full in vivo characterization in detail.