2. Academic Validation
  3. Identification of a novel DGKα inhibitor for XLP-1 therapy by virtual screening

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

  • Eur J Med Chem. 2019 Feb 15;164:378-390. doi: 10.1016/j.ejmech.2018.12.061.
Suresh Velnati 1,  Elisa Ruffo 2,  Alberto Massarotti 3,  Maria Talmon 4,  Konduru Sai Sandeep Varma 1,  Alessandro Gesu 3,  Luigia Grazia Fresu 4,  Andrew L Snow 5,  Alessandra Bertoni 1,  Daniela Capello 1,  Gian Cesare Tron 3,  Andrea Graziani 6,  Gianluca Baldanzi 7
Affiliations

Affiliations

  • 1 Department of Translational Medicine and Center for Translational Research on Autoimmune and Allergic Diseases (CAAD), University of Piemonte Orientale, 28100, Novara, Italy.
  • 2 School of Medicine, University Vita e Salute San Raffaele, 20132, Milan, Italy.
  • 3 Department of Pharmaceutical Science, University of Piemonte Orientale, 28100, Novara, Italy.
  • 4 Department of Health Sciences, School of Medicine, University of Piemonte Orientale, 28100, Novara, Italy.
  • 5 Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.
  • 6 School of Medicine, University Vita e Salute San Raffaele, 20132, Milan, Italy. Electronic address: graziani.andrea@unisr.it.
  • 7 Department of Translational Medicine and Center for Translational Research on Autoimmune and Allergic Diseases (CAAD), University of Piemonte Orientale, 28100, Novara, Italy. Electronic address: gianluca.baldanzi@med.uniupo.it.
PMID: 30611057 DOI: 10.1016/j.ejmech.2018.12.061
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.

Keywords

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

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