A high-content subtractive screen for selecting small molecules affecting internalization of GPCRs

Yong Jun Kwon, Weontae Lee, Auguste Genovesio, Neil Emans

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3 Citations (Scopus)


G-protein-coupled receptors (GPCRs) are pivotal in cellular responses to the environment and are common drug targets. Identification of selective small molecules acting on single GPCRs is complicated by the shared machinery coupling signal transduction to physiology. Here, we demonstrate a high-content screen using a panel of GPCR assays to identify receptor selective molecules acting within the kinase/phosphatase inhibitor family. A collection of 88 kinase and phosphatase inhibitors was screened against seven agonist-induced GPCR internalization cell models as well as transferrin uptake in human embryonic kidney cells. Molecules acting on a single receptor were identified through excluding pan-specific compounds affecting housekeeping endocytosis or disrupting internalization of multiple receptors. We identified compounds acting on a sole GPCR from activities in a broad range of chemical structures that could not be easily sorted by conventional means. Selective analysis can therefore rapidly select compounds selectively affecting GPCR activity with specificity to one receptor class through high-content screening.

Original languageEnglish
Pages (from-to)379-385
Number of pages7
JournalJournal of Biomolecular Screening
Issue number3
Publication statusPublished - 2012 Mar

Bibliographical note

Funding Information:
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST; No. 2011-00244), Gyeonggi-do, KISTI, and by parliamentary grant and Department of Science and Technology support in South Africa (to N.E.).

All Science Journal Classification (ASJC) codes

  • Analytical Chemistry
  • Biotechnology
  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery


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