New brain-penetrating RIPK2 inhibitor prodrug for GBM

INDICATION: Brain cancer

Cell culture and mouse studies identified a brain-penetrating naphthoquinone-based prodrug of a RIPK2 inhibitor that could help treat glioblastoma multiforme (GBM). Screening a library of drug-like small molecules in three human GBM cell lines identified a naphthoquinone-based compound that inhibited cell viability with greater potency than the generic chemotherapy temozolomide (EC₅₀ values = 0.22-0.89 μM and >20 μM, respectively). In an orthotopic patient-derived xenograft (PDX) mouse model of GBM, the compound decreased tumor growth compared with vehicle. Additional in vitro and GBM cell line-based testing identified a metabolite of the compound that inhibited cell viability with EC₅₀ values of 63-290 nM and bound RIPK2 with a K_d of 2.3 μM, suggesting the compound is a prodrug of a RIPK2 inhibitor. In mice, the compound had a brain-to-plasma ratio of 0.319. Next steps could include evaluating the safety of the prodrug in animal models of GBM...