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Kinase-Modulated Bioluminescent Indicators Enable Noninvasive Imaging of Drug Activity in the Brain
Yan Wu1,2, Joel R Walker3, Michael Westberg1,2,4
1Department of Bioengineering, Stanford University, Stanford, California 94305, United States.
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.
Insights
New bioluminescent indicators (KiMBIs) allow noninvasive imaging of drug activity in the brain. This technology helps identify effective brain-penetrant kinase inhibitors for treating neurological diseases.
Area of Science:
- Neuroscience
- Pharmacology
- Biotechnology
Background:
- Aberrant kinase activity is implicated in brain diseases like cancer and neurodegeneration.
- The blood-brain barrier hinders drug delivery, making brain kinase inhibitor efficacy difficult to assess.
- Current methods for assessing brain drug activity are invasive and time-consuming.
Purpose of the Study:
- To develop a noninvasive method for imaging drug activity within the brain.
- To create a novel bioluminescent indicator for the Ras-Raf-MEK-ERK pathway.
- To enable rapid screening and pharmacodynamic characterization of brain-penetrant kinase inhibitors.
Main Methods:
- Development of kinase-modulated bioluminescent indicators (KiMBIs) using a luciferase-luciferin system.
- Creation of an ERK KiMBI to monitor inhibitors of the Ras-Raf-MEK-ERK pathway.
- In vivo validation in xenograft models and native brain tissues to assess drug penetration and target engagement.
Main Results:
- The ERK KiMBI successfully distinguished between brain-penetrant and nonpenetrant MEK inhibitors.
- KiMBIs revealed blood-tumor barrier permeability in xenograft models.
- Pharmacodynamic activity of MEK inhibitors was reported in both native brain and intracranial xenografts.
- Screening identified temuterkib as a promising brain-active ERK inhibitor, unpredicted by its chemical properties.
Conclusions:
- KiMBIs provide a noninvasive, longitudinal imaging approach for assessing drug activity in the brain.
- This technology facilitates the identification and characterization of kinase inhibitors for brain diseases.
- KiMBIs overcome limitations of traditional methods, accelerating the development of therapeutics for neurological disorders.
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