Identification of a novel DGKα inhibitor for XLP-1 therapy by virtual screening

Suresh Velnati, Elisa Ruffo, Alberto Massarotti, Maria Talmon, Konduru Sai Sandeep Varma, Alessandro Gesu, Luigia Grazia Fresu, Andrew L. Snow, Alessandra Bertoni, Daniela Capello, Gian Cesare Tron, Andrea Graziani, Gianluca Baldanzi

Research output: Contribution to journalArticle

Abstract

As part of an effort to identify druggable diacylglycerol kinase alpha (DGKα) inhibitors, we used an in-silico approach based on chemical homology with the two commercially available DGKα inhibitors R59022 and R59949. Ritanserin and compound AMB639752 emerged from the screening of 127 compounds, showing an inhibitory activity superior to the two commercial inhibitors, being furthermore specific for the alpha isoform of diacylglycerol kinase. Interestingly, AMB639752 was also devoid of serotoninergic activity. The ability of both ritanserin and AMB639752, by inhibiting DGKα in intact cells, to restore restimulation induced cell death (RICD) in SAP deficient lymphocytes was also tested. Both compounds restored RICD at concentrations lower than the two previously available inhibitors, indicating their potential use for the treatment of X-linked lymphoproliferative disease 1 (XLP-1), a rare genetic disorder in which DGKα activity is deregulated.

Original languageEnglish
Pages (from-to)378-390
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume164
DOIs
Publication statusPublished - Feb 15 2019

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Keywords

  • Diacylglycerol kinase
  • In silico screening
  • Lipid second messenger
  • Signal transduction
  • X-linked lymphoproliferative disease 1

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Velnati, S., Ruffo, E., Massarotti, A., Talmon, M., Varma, K. S. S., Gesu, A., Fresu, L. G., Snow, A. L., Bertoni, A., Capello, D., Tron, G. C., Graziani, A., & Baldanzi, G. (2019). Identification of a novel DGKα inhibitor for XLP-1 therapy by virtual screening. European Journal of Medicinal Chemistry, 164, 378-390. https://doi.org/10.1016/j.ejmech.2018.12.061