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Achieving sufficient unbound brain exposure while maintaining potent target inhibition is a major challenge in small-molecule drug discovery. This poster presents IRBM’s integrated medicinal chemistry, pharmacology, and drug metabolism and pharmacokinetics strategy for an SHP2 inhibitor program. Compounds progress through a cascade that links CNS-relevant physicochemical design, complementary in vitro blood-brain barrier models, and in vivo rodent pharmacokinetics, using unbound brain exposure rather than potency alone to guide prioritization. This resource-efficient approach supported the selection of I-1000233, a brain-penetrant allosteric SHP2 inhibitor that achieves CNS exposure and efficacy in an orthotopic glioblastoma model. Download the poster to explore the optimization cascade, exposure data, and in vivo results in detail.
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SHP2 BrainPenetrant DMPK Cascade poster, code 26019