title: Quantifying the CDK inhibitor VMY-1-103's activity and tissue levels in an in vivo tumor model by LC-MS/MS and by MRI.
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.
authors.affiliation: Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Sirajuddin
authors.forename: Sudeep
authors.initials: S
authors.lastname: Das
authors.forename: Lymor
authors.initials: L
authors.lastname: Ringer
authors.forename: Olga C
authors.initials: OC
authors.lastname: Rodriguez
authors.forename: Angiela
authors.initials: A
authors.lastname: Sivakumar
authors.forename: Yi-Chien
authors.initials: YC
authors.lastname: Lee
authors.forename: Aykut
authors.initials: A
authors.lastname: Üren
authors.forename: Stanley T
authors.initials: ST
authors.lastname: Fricke
authors.forename: Brian
authors.initials: B
authors.lastname: Rood
authors.forename: Alpay
authors.initials: A
authors.lastname: Ozcan
authors.forename: Sean S
authors.initials: SS
authors.lastname: Wang
authors.forename: Sana
authors.initials: S
authors.lastname: Karam
authors.forename: Venkata
authors.initials: V
authors.lastname: Yenugonda
authors.forename: Patricia
authors.initials: P
authors.lastname: Salinas
authors.forename: Emanuel
authors.initials: E
authors.lastname: Petricoin
authors.forename: Michael
authors.initials: M
authors.lastname: Pishvaian
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Richard
authors.initials: R
authors.lastname: Schlegel
authors.forename: Bahram
authors.initials: B
authors.lastname: Moasser
authors.forename: Chris
authors.initials: C
authors.lastname: Albanese
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D002453:Cell Cycle / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002853:Chromatography, Liquid; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D003619:Dansyl Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008527:Medulloblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry
chemical_list: C557984:2-chloro-N-(2-(5-(dimethylamino)naphthalene-1-sulfonamido)ethyl)-4-(2-(1-hydroxy-3-methylbutan-2-ylamino)-9-isopropyl-9H-purin-6-ylamino)benzamide; D000970:Antineoplastic Agents; D003619:Dansyl Compounds; D047428:Protein Kinase Inhibitors; C113584:purvalanol B; D018844:Cyclin-Dependent Kinases; D000225:Adenine