Abstract 463: Preclinical evaluation of CNS drug penetration of a novel series of MTA-cooperative PRMT5 inhibitors including TNG456

Abstract Treatment of brain tumors and brain metastases remains a significant unmet medical need. This is especially true for high-grade gliomas, where up to 50% of cases exhibit loss of MTAP, creating a dependency on PRMT5 and a susceptibility to MTA-cooperative PRMT5 inhibitors. For preclinical drug discovery, the accurate prediction of drug exposure in the human CNS compartment is therefore of critical importance. This study evaluates the utility of preclinical models, specifically the monkey cerebrospinal fluid (CSF) model, alongside the physicochemical properties of compounds, including permeability and efflux characteristics, to predict free brain drug exposure in humans. The non-terminal monkey CSF model permits assessment of CNS penetration with minimal invasiveness. Complementary to this, as part of the 14-day terminal dose range finding toxicology studies, brain tissues were collected at necropsy to verify and correlate predicted brain penetration with actual exposure levels. Our findings demonstrate a strong correlation between CSF concentrations in the monkey model and free brain drug exposure, suggesting that incorporating these datapoints, in addition to optimizing permeability and efflux properties, enhances the reliability of CNS drug delivery predictions. This research highlights the importance of integrating non-terminal preclinical models and physicochemical analysis to improve the safety and efficacy of CNS-targeted therapeutics. In addition, utility of rodent terminal brain drug exposure models and the importance of deriving unbound free brain drug exposures will be discussed. Citation Format: Alice Tsai, Charles B. Davis, Kimberly J. Briggs, Kevin M. Cottrell, John P. Maxwell, Adam S. Crystsal, Ellen Hooper, Jannik N. Andersen. Preclinical evaluation of CNS drug penetration of a novel series of MTA-cooperative PRMT5 inhibitors including TNG456 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 463.