Delivery versus Potency in Treating Brain Tumors: BI-907828, a MDM2-p53 Antagonist with Limited BBB Penetration but Significant In Vivo Efficacy in Glioblastoma.

ABSTRACT: MDM2-p53 inhibition may be effective in glioblastoma (GBM). This study evaluates the pharmacokinetics/pharmacodynamics of BI-907828, a potent antagonist of MDM2, in GBM, and demonstrates a translational paradigm with a focus on a unified "Delivery - Potency - Efficacy" relationship in drug development for central nervous system(CNS) tumors. BI-907828 was tested for cytotoxicity and MDM2-p53 pathway inhibition. Systemic pharmacokinetics and transport mechanisms controlling CNS distribution were evaluated in mice. BI-907828 free fractions in cell media, mouse and human specimens were measured to determine "active" unbound concentrations. Efficacy measures, including overall survival and target expression were assessed in mouse orthotopic GBM xenografts. BI-907828 exhibited potent inhibition

SUBMITTER: Zhang W 

PROVIDER: S-EPMC10843165 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature