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Kinase-Modulated Bioluminescent Indicators Enable Noninvasive Imaging of Drug Activity in the Brain.

ABSTRACT: Aberrant kinase activity contributes to the pathogenesis of brain cancers, neurodegeneration, and neuropsychiatric diseases, but identifying kinase inhibitors that function in the brain is challenging. Drug levels in blood do not predict efficacy in the brain because the blood-brain barrier prevents entry of most compounds. Rather, assessing kinase inhibition in the brain requires tissue dissection and biochemical analysis, a time-consuming and resource-intensive process. Here, we report kinase-modulated bioluminescent indicators (KiMBIs) for noninvasive longitudinal imaging of drug activity in the brain based on a recently optimized luciferase-luciferin system. We develop an ERK KiMBI to report inhibitors of the Ras-Raf-MEK-ERK pathway, for which no bioluminescent indicators previously existed. ERK KiMBI discriminates between brain-penetrant and nonpenetrant MEK inhibitors, reveals blood-tumor barrier leakiness in xenograft models, and reports MEK inhibitor pharmacodynamics in native brain tissues and intracranial xenografts. Finally, we use ERK KiMBI to screen ERK inhibitors for brain efficacy, identifying temuterkib as a promising brain-active ERK inhibitor, a result not predicted from chemical characteristics alone. Thus, KiMBIs enable the rapid identification and pharmacodynamic characterization of kinase inhibitors suitable for treating brain diseases.

SUBMITTER: Wu Y

PROVIDER: S-EPMC10141594 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Kinase-Modulated Bioluminescent Indicators Enable Noninvasive Imaging of Drug Activity in the Brain.

Wu Yan Y Walker Joel R JR Westberg Michael M Ning Lin L Monje Michelle M Kirkland Thomas A TA Lin Michael Z MZ Su Yichi Y

ACS central science 20230320 4

Aberrant kinase activity contributes to the pathogenesis of brain cancers, neurodegeneration, and neuropsychiatric diseases, but identifying kinase inhibitors that function in the brain is challenging. Drug levels in blood do not predict efficacy in the brain because the blood-brain barrier prevents entry of most compounds. Rather, assessing kinase inhibition in the brain requires tissue dissection and biochemical analysis, a time-consuming and resource-intensive process. Here, we report kinase- ...[more]

PMID: 37122464

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Project description:BackgroundIn recent years, it has become increasingly apparent that characterizing individual brain structure, connectivity and dynamics is essential for understanding brain function in health and disease. However, the majority of neuroimaging and brain stimulation research has characterized human brain function by averaging measurements from groups of subjects and providing population-level inferences. External perturbations applied directly to well-defined brain regions can reveal distinctive information about the state, connectivity and dynamics of the human brain at the individual level.ObjectivesIn a series of studies, we aimed to characterize individual brain responses to MRI-guided transcranial magnetic stimulation (TMS), and explore the reproducibility of the evoked effects, differences between brain regions, and their individual specificity.MethodsIn the first study, we administered single pulses of TMS to both anatomically (left dorsolateral prefrontal cortex- 'L-DLPFC', left Intra-parietal lobule- 'L-IPL) and functionally (left motor cortex- 'L-M1', right default mode network- 'R-DMN, right dorsal attention network- 'R-DAN') defined cortical nodes in the frontal, motor, and parietal regions across two identical sessions spaced one month apart in 24 healthy volunteers. In the second study, we extended our analyses to two independent data sets (n = 10 in both data sets) having different sham-TMS protocols.ResultsIn the first study, we found that perturbation-induced cortical propagation patterns are heterogeneous across individuals but highly reproducible within individuals, specific to the stimulated region, and distinct from spontaneous activity. Most importantly, we demonstrate that by assessing the spatiotemporal characteristics of TMS-induced brain responses originating from different cortical regions, individual subjects can be identified with perfect accuracy. In the second study, we demonstrated that subject specificity of TEPs is generalizable across independent data sets and distinct from non-transcranial neural responses evoked by sham-TMS protocols.ConclusionsPerturbation-induced brain responses reveal unique "brain fingerprints" that reflect causal connectivity dynamics of the stimulated brain regions, and may serve as reliable biomarkers of individual brain function.

Dataset Information

Kinase-Modulated Bioluminescent Indicators Enable Noninvasive Imaging of Drug Activity in the Brain.

Publications

Kinase-Modulated Bioluminescent Indicators Enable Noninvasive Imaging of Drug Activity in the Brain.

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