TY - JOUR
T1 - Identification of a novel DGKα inhibitor for XLP-1 therapy by virtual screening
AU - Velnati, Suresh
AU - Ruffo, Elisa
AU - Massarotti, Alberto
AU - Talmon, Maria
AU - Varma, Konduru Sai Sandeep
AU - Gesu, Alessandro
AU - Fresu, Luigia Grazia
AU - Snow, Andrew L.
AU - Bertoni, Alessandra
AU - Capello, Daniela
AU - Tron, Gian Cesare
AU - Graziani, Andrea
AU - Baldanzi, Gianluca
PY - 2019/2/15
Y1 - 2019/2/15
N2 - 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.
AB - 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.
KW - Diacylglycerol kinase
KW - In silico screening
KW - Lipid second messenger
KW - Signal transduction
KW - X-linked lymphoproliferative disease 1
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UR - http://www.scopus.com/inward/citedby.url?scp=85059340170&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2018.12.061
DO - 10.1016/j.ejmech.2018.12.061
M3 - Article
C2 - 30611057
AN - SCOPUS:85059340170
VL - 164
SP - 378
EP - 390
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -