MDM2-p53 inhibition may be effective in glioblastoma. This study evaluates the PK/PD 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 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 of MDM2-p53 pathway and promoted cell death in GBM TP53 wild-type cells. MDM2-amplified cells are highly sensitive to BI-907828, with an effective unbound concentration of 0.1 nM. The CNS distribution of BI-907828 is limited by BBB efflux mediated by P-gp, resulting in a Kp,uu_brain of 0.002. Despite this seemingly “poor” BBB penetration, weekly administration of 10 mg/kg BI-907828 extended median survival of orthotopic GBM108 xenografts from 28 to 218 days (P < 0.0001). This excellent efficacy can be attributed to high potency, resulting in a limited, yet effective, exposure in the CNS. These studies show that efficacy of BI-907828 in orthotopic models is related to high potency even though its CNS distribution is limited by BBB efflux. Therefore, a comprehensive understanding of all aspects of the “Delivery – Potency – Efficacy” relationship is warranted in drug discovery and development, especially for treatment of CNS tumors.

中文翻译：

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治疗脑肿瘤的递送与效力：BI-907828，一种 MDM2-p53 拮抗剂，其 BBB 渗透有限，但对胶质母细胞瘤具有显着的体内疗效

MDM2-p53 抑制可能对胶质母细胞瘤有效。本研究评估了 BI-907828（一种有效的 MDM2 拮抗剂）在 GBM 中的 PK/PD，并展示了一种转化范式，重点关注 CNS 肿瘤药物开发中统一的“递送 - 效力 - 功效”关系。测试了 BI-907828 的细胞毒性和 MDM2-p53 通路抑制。在小鼠中评估了控制中枢神经系统分布的全身药代动力学和转运机制。测量细胞培养基、小鼠和人类样本中的 BI-907828 游离部分以确定“活性”未结合浓度。在小鼠原位 GBM 异种移植物中评估了疗效指标，包括总体存活率和靶标表达。BI-907828 表现出对 MDM2-p53 通路的有效抑制并促进 GBM TP53 野生型细胞的细胞死亡。MDM2 扩增细胞对 BI-907828 高度敏感，有效未结合浓度为 0.1 nM。BI-907828 的 CNS 分布受到 P-gp 介导的 BBB 流出的限制，导致 Kp,uu_brain 为 0.002。尽管 BBB 渗透看似“差”，但每周施用 10 mg/kg BI-907828 将原位 GBM108 异种移植物的中位生存期从 28 天延长至 218 天（P < 0.0001）。这种优异的功效可归因于高效力，导致中枢神经系统的暴露有限但有效。这些研究表明，BI-907828 在原位模型中的功效与高效力相关，尽管其 CNS 分布受到 BBB 流出的限制。因此，在药物发现和开发中，特别是在中枢神经系统肿瘤的治疗中，有必要全面了解“递送-效价-功效”关系的各个方面。