Photochemical Modulation of Ras-Mediated Signal Transduction Using Caged Farnesyltransferase Inhibitors: Activation by One- and Two-Photon Excitation

Daniel Abate-Pella, Nicholette A. Zeliadt, Joshua D. Ochocki, Janel K. Warmka, Timothy M. Dore, David A. Blank, Elizabeth V. Wattenberg, Mark D. Distefano

Research output: Contribution to journalArticlepeer-review

Abstract

The creation of caged molecules involves the attachment of protecting groups to biologically active compounds such as ligands, substrates and drugs that can be removed under specific conditions. Photoremovable caging groups are the most common due to their ability to be removed with high spatial and temporal resolution. Here, the synthesis and photochemistry of a caged inhibitor of protein farnesyltransferase is described. The inhibitor, FTI, was caged by alkylation of a critical thiol group with a bromohydroxycoumarin (Bhc) moiety. While Bhc is well established as a protecting group for carboxylates and phosphates, it has not been extensively used to cage sulfhydryl groups. The resulting caged molecule, Bhc-FTI, can be photolyzed with UV light to release the inhibitor that prevents Ras farnesylation, Ras membrane localization and downstream signaling. Finally, it is shown that Bhc-FTI can be uncaged by two-photon excitation to produce FTI at levels sufficient to inhibit Ras localization and alter cell morphology. Given the widespread involvement of Ras proteins in signal transduction pathways, this caged inhibitor should be useful in a plethora of studies.

Original languageEnglish (US)
Pages (from-to)1009-1016
Number of pages8
JournalChemBioChem
Volume13
Issue number7
DOIs
StatePublished - May 7 2012

Keywords

  • Bromohydroxycoumarin
  • Caged thiol
  • Enzyme inhibitor
  • Farnesylation
  • Photochemistry
  • Ras

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

Fingerprint Dive into the research topics of 'Photochemical Modulation of Ras-Mediated Signal Transduction Using Caged Farnesyltransferase Inhibitors: Activation by One- and Two-Photon Excitation'. Together they form a unique fingerprint.

Cite this