PO.TB02.01 · 肿瘤生物学
通过一种具有 BBB 可透过底物的激酶调控生物发光指示剂揭示 Akt 药物的药效动力学
Pharmacodynamics of Akt drugs revealed by a kinase-modulatedbioluminescent indicator withBBB-permeable substrate
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摘要 Abstract
中文摘要
能够在活体对象中实时可视化生物学事件的非侵入性成像工具在生物医学研究中极具价值。生物发光成像（BLI）以其高灵敏度和低背景，为开发在体内监测细胞内信号转导的分子传感器提供了理想平台。在此，我们报告了一种激酶调控生物发光指示剂（KiMBI）的开发，用于对 Akt 靶向治疗药物进行快速、非侵入性的药效动力学（PD）评估，从而大幅减少化合物用量和动物需求。这种不依赖 ATP 的报告基因基于 NanoLuc 荧光素酶，在给予可穿透脑组织的底物 cephalofurimazine（CFz9）后发光。利用 KiMBI，我们通过设计并表征两种新型类似物，对具有脑活性的 Akt 抑制剂 ipatasertib 进行了结构-药效动力学关系分析。其中一种类似物 ML-B01 在脑组织和外周组织中均表现出强效的 Akt 抑制作用。值得注意的是，capivasertib、ipatasertib 和 ML-B01 均表现出超过其药代动力学（PK）特征的持久 PD 效应。此外，KiMBI 成像揭示，一种 Akt 靶向的蛋白水解靶向嵌合体（PROTAC）降解剂的 PD 效应在单次给药后持续超过三天。综上所述，这些结果确立了使用 Akt KiMBI 的生物发光成像是一种灵敏而高效的方法，可在体内实时、纵向可视化 Akt 抑制剂和降解剂的活性。该平台为早期药物优化以及在活体动物中阐明激酶靶向疗法的药效动力学提供了强有力的方法。
查看英文原文 English abstract
Noninvasive imaging tools that enable real-time visualization of biological events in living subjects are highly valuable in biomedical research. Bioluminescence imaging (BLI), with its high sensitivity and low background, provides an ideal platform for developing molecular sensors to monitor intracellular signaling in vivo . Here, we report the development of a kinase-modulated bioluminescent indicator (KiMBI) for rapid, noninvasive pharmacodynamic (PD) assessment of Akt-targeted therapeutics, substantially reducing compound use and animal requirements. This ATP-independent reporter, based on NanoLuc luciferase, produces light upon administration of the brain-penetrant substrate cephalofurimazine (CFz9). Using KiMBI, we performed a structure-PD relationship analysis of the brain-active Akt inhibitor ipatasertib by designing and characterizing two novel analogs. One analog, ML-B01, exhibited robust Akt inhibition in both brain and peripheral tissues. Remarkably, capivasertib, ipatasertib, and ML-B01 all demonstrated prolonged PD effects that outlasted their pharmacokinetic (PK) profiles. Furthermore, KiMBI imaging revealed that the PD effect of an Akt-targeted proteolysis-targeting chimera (PROTAC) degrader persisted for more than three days following a single dose. Together, these results establish bioluminescence imaging with the Akt KiMBI as a sensitive and efficient method for real-time, longitudinal visualization of Akt inhibitor and degrader activity in vivo. This platform offers a powerful approach for early-stage drug optimization and for elucidating the pharmacodynamics of kinase-targeted therapies in live animals.
利益披露 Disclosure
Y. Wu, None..
C. Hao, None..
C. Gao, None..
M. Hageman, None..
S. Lee, None..
T. A. Kirkland, None..
N. S. Gray, None..
Y. Su, None..
M. Z. Lin, None.