A fluorescent reporter of ATP binding-competent receptor kinases

Renaud Sicard, Jyothi Dhuguru, Wenjun Liu, Nirav Patel, Ralf Landgraf, James N. Wilson

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

ERBB receptor kinases play a crucial role in normal development and cancer malignancies. A broad range of modifications creates receptor subpopulations with distinct functional properties in live cells. Their apparent activation state, typically assayed by tyrosine phosphorylation of substrates, reflects a complex equilibrium of competing reactions. With the aim of developing optical tools to investigate ERBB populations and their state of activation, we have synthesized a fluorescent 'turn-on' probe, DMAQ, targeting the ERBB ATP binding pocket. Upon binding, probe emission increases due to the hydrophobic environment and restricted geometry of the ERBB2 kinase domain, facilitating the analysis of receptor states at low occupancy and without the removal of unbound probes. Cellular ERBB2 autophosphorylation is inhibited with saturation kinetics that correlate with the increase in probe fluorescence. Thus, DMAQ is an example of a new generation of 'turn-on' probes with potential applications in querying receptor kinase populations both in vitro and in live cells.

Original languageEnglish (US)
Pages (from-to)5532-5535
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number17
DOIs
StatePublished - Sep 1 2012

Keywords

  • EGFR
  • ERBB2
  • Fluorescent probes
  • Kinase inhibitors
  • Quinazoline

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

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