Abstract
The development of new small molecule-based therapeutic drugs requires accurate quantification of drug bioavailability, biological activity and treatment efficacy. Rapidly measuring these endpoints is often hampered by the lack of efficient assay platforms with high sensitivity and specificity. Using an in vivo model system, we report a simple and sensitive liquid chromatography-tandem mass spectrometry assay to quantify the bioavailability of a recently developed novel cyclin-dependent kinase inhibitor VMY-1-103, a purvalanol B-based analog whose biological activity is enhanced via dansylation. We developed a rapid organic phase extraction technique and validated wide and functional VMY-1-103 distribution in various mouse tissues, consistent with its enhanced potency previously observed in a variety of human cancer cell lines. More importantly, in vivo MRI and single voxel proton MR-Spectroscopy further established that VMY-1-103 inhibited disease progression and affected key metabolites in a mouse model of hedgehog-driven medulloblastoma.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenine / analogs & derivatives*
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Adenine / chemistry
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Adenine / pharmacokinetics
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Adenine / pharmacology
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Animals
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology*
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Biological Availability
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Cell Cycle / drug effects
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Cerebellar Neoplasms / drug therapy*
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Cerebellar Neoplasms / genetics
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Cerebellar Neoplasms / metabolism
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Chromatography, Liquid
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Cyclin-Dependent Kinases / genetics
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Cyclin-Dependent Kinases / metabolism
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Dansyl Compounds / pharmacokinetics
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Dansyl Compounds / pharmacology*
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Humans
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Magnetic Resonance Imaging
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Medulloblastoma / drug therapy*
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Medulloblastoma / genetics
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Medulloblastoma / metabolism
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Mice
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology*
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Tandem Mass Spectrometry
Substances
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2-chloro-N-(2-(5-(dimethylamino)naphthalene-1-sulfonamido)ethyl)-4-(2-(1-hydroxy-3-methylbutan-2-ylamino)-9-isopropyl-9H-purin-6-ylamino)benzamide
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Antineoplastic Agents
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Dansyl Compounds
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Protein Kinase Inhibitors
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purvalanol B
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Cyclin-Dependent Kinases
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Adenine