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

Paul Sirajuddin, Sudeep Das, Lymor Ringer, Olga C. Rodriguez, Angiela Sivakumar, Yi Chien Lee, Aykut Üren, Stanley T. Fricke, Brian Rood, Alpay Ozcan, Sean S. Wang, Sana Karam, Venkata Yenugonda, Patricia Salinas, Emanuel Petricoin, Michael Pishvaian, Michael P. Lisanti, Yue Wang, Richard Schlegel, Bahram MoasserChris Albanese

Research output: Contribution to journalArticlepeer-review

Abstract

The development of new small molecule-based therapeutic drugs requires accurate quantifcation of drug bioavailability, biological activity and treatment efcacy. Rapidly measuring these endpoints is often hampered by the lack of efcient assay platforms with high sensitivity and specifcity. 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 afected key metabolites in a mouse model of hedgehog-driven medulloblastoma.

Original languageEnglish (US)
Pages (from-to)3801-3809
Number of pages9
JournalCell Cycle
Volume11
Issue number20
DOIs
StatePublished - Oct 15 2012
Externally publishedYes

Keywords

  • Animal models
  • CDK inhibitor
  • MR-Spectroscopy
  • MRI
  • Medulloblastoma
  • Prostate
  • Tandem mass spectrometry

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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