{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T14:14:15Z","timestamp":1766067255634,"version":"build-2065373602"},"reference-count":53,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2020,12,21]],"date-time":"2020-12-21T00:00:00Z","timestamp":1608508800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The store-operated calcium entry, better known as SOCE, forms the main Ca2+ influx pathway in non-excitable cells, especially in leukocytes, where it is required for cell activation and the immune response. During the past decades, several inhibitors were developed, but they lack specificity or efficacy. From the non-specific SOCE inhibitor 2-aminoethyl diphenylborinate (2-APB), we synthetized 16 new analogues by replacing\/modifying the phenyl groups. Among them, our compound P11 showed the best inhibitory capacity with a Ki \u2248 75 nM. Furthermore, below 1 \u00b5M, P11 was devoid of any inhibitory activity on the two other main cellular targets of 2-APB, the IP3 receptors, and the SERCA pumps. Interestingly, Jurkat T cells secrete interleukin-2 under phytohemagglutinin stimulation but undergo cell death and stop IL-2 synthesis when stimulated in the presence of increasing P11 concentrations. Thus, P11 could represent the first member of a new and potent family of immunosuppressors.<\/jats:p>","DOI":"10.3390\/ijms21249777","type":"journal-article","created":{"date-parts":[[2020,12,21]],"date-time":"2020-12-21T20:42:01Z","timestamp":1608583321000},"page":"9777","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Synthesis and Characterization of Store-Operated Calcium Entry Inhibitors Active in the Submicromolar Range"],"prefix":"10.3390","volume":"21","author":[{"given":"Camille","family":"Le Guilcher","sequence":"first","affiliation":[{"name":"Physiopathog\u00e9n\u00e8se et Traitements des Maladies du Foie, Universit\u00e9 Paris-Saclay, Rue des Adeles, 91405 Orsay, France"},{"name":"INSERM U1193, Rue des Adeles, 91405 Orsay, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2028-818X","authenticated-orcid":false,"given":"Tomas","family":"Luyten","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine &amp; Leuven Kanker Instituut, B-3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3591-4967","authenticated-orcid":false,"given":"Jan B.","family":"Parys","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine &amp; Leuven Kanker Instituut, B-3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7001-2803","authenticated-orcid":false,"given":"Mathieu","family":"Pucheault","sequence":"additional","affiliation":[{"name":"Institute of Molecular Science, CNRS, Universit\u00e9 de Bordeaux, 33400 Talence, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0377-9163","authenticated-orcid":false,"given":"Olivier","family":"Dellis","sequence":"additional","affiliation":[{"name":"Physiopathog\u00e9n\u00e8se et Traitements des Maladies du Foie, Universit\u00e9 Paris-Saclay, Rue des Adeles, 91405 Orsay, France"},{"name":"INSERM U1193, Rue des Adeles, 91405 Orsay, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/35036035","article-title":"The versatility and universality of calcium signalling","volume":"1","author":"Berridge","year":"2000","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1152\/physrev.00057.2003","article-title":"Store-Operated Calcium Channels","volume":"85","author":"Parekh","year":"2005","journal-title":"Physiol. Rev."},{"key":"ref_3","first-page":"179","article-title":"A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function","volume":"441","author":"Feske","year":"2006","journal-title":"Nat. Cell Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1124\/mi.10.4.4","article-title":"Pharmacology of Store-operated Calcium Channels","volume":"10","author":"Putney","year":"2010","journal-title":"Mol. Interv."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1124\/mol.105.015701","article-title":"2-Aminoethoxydiphenyl Borate as a Prototype Drug for a Group of Structurally Related Calcium Channel Blockers in Human Platelets","volume":"69","author":"Dobrydneva","year":"2005","journal-title":"Mol. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ceca.2009.10.004","article-title":"Two novel 2-aminoethyl diphenylborinate (2-APB) analogues differentially activate and inhibit store-operated Ca2+ entry via STIM proteins","volume":"47","author":"Goto","year":"2010","journal-title":"Cell Calcium."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2341","DOI":"10.1016\/j.bbamcr.2014.03.012","article-title":"Characterization of novel store-operated calcium entry effectors","volume":"1843","author":"Djillani","year":"2014","journal-title":"Biochim. et Biophys. Acta (BBA) - Bioenerg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.1469-7793.2001.t01-1-00003.x","article-title":"Potentiation and inhibition of Ca2+ release-activated Ca2+ channels by 2-aminoethyldiphenyl borate (2-APB) occurs independently of IP3 receptors","volume":"536","author":"Prakriya","year":"2001","journal-title":"J. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.ceca.2015.04.005","article-title":"Potentiation of the store-operated calcium entry (SOCE) induces phytohemagglutinin-activated Jurkat T cell apoptosis","volume":"58","author":"Djillani","year":"2015","journal-title":"Cell Calcium."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.ceca.2017.01.015","article-title":"DPB162-AE, an inhibitor of store-operated Ca2+ entry, can deplete the endoplasmic reticulum Ca2+ store","volume":"62","author":"Bittremieux","year":"2017","journal-title":"Cell Calcium."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Schild, A., Bhardwaj, R., Wenger, N., Tscherrig, D., Kandasamy, P., Derni\u010d, J., Baur, R., Peinelt, C., Hediger, M.A., and Lochner, M. (2020). Synthesis and Pharmacological Characterization of 2-Aminoethyl Diphenylborinate (2-APB) Derivatives for Inhibition of Store-Operated Calcium Entry (SOCE) in MDA-MB-231 Breast Cancer Cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21165604"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6915","DOI":"10.1074\/jbc.M107755200","article-title":"Modification of Store-operated Channel Coupling and Inositol Trisphosphate Receptor Function by 2-Aminoethoxydiphenyl Borate in DT40 Lymphocytes","volume":"277","author":"Ma","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1096\/fj.02-0037rev","article-title":"2-aminoethoxydiphenyl borate (2-APB) is a reliable blocker of store-operated Ca2+ entry but an inconsistent inhibitor of InsP3-induced Ca2+ release","volume":"16","author":"Bootman","year":"2002","journal-title":"FASEB J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1054\/ceca.2000.0163","article-title":"2-Aminoethoxydiphenyl borate affects the inositol 1,4,5-trisphosphate receptor, the intracellular Ca2+pump and the non-specific Ca2+leak from the non-mitochondrial Ca2+stores in permeabilized A7r5 cells","volume":"29","author":"Missiaen","year":"2001","journal-title":"Cell Calcium."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/S0143-4160(03)00026-5","article-title":"2-Aminoethoxydiphenyl borate (2-APB) antagonises inositol 1,4,5-trisphosphate-induced calcium release, inhibits calcium pumps and has a use-dependent and slowly reversible action on store-operated calcium entry channels","volume":"34","author":"Peppiatt","year":"2003","journal-title":"Cell Calcium."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"19265","DOI":"10.1074\/jbc.M801535200","article-title":"Complex Actions of 2-Aminoethyldiphenyl Borate on Store-operated Calcium Entry","volume":"283","author":"DeHaven","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3061","DOI":"10.1113\/jphysiol.2008.151365","article-title":"2-Aminoethoxydiphenyl borate directly facilitates and indirectly inhibits STIM1-dependent gating of CRAC channels","volume":"586","author":"Peinelt","year":"2008","journal-title":"J. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"17662","DOI":"10.1074\/jbc.M801536200","article-title":"Store-dependent and -independent Modes Regulating Ca2+Release-activated Ca2+Channel Activity of Human Orai1 and Orai3","volume":"283","author":"Zhang","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_19","first-page":"1311","article-title":"Faculty Opinions recommendation of ORAI1 deficiency and lack of store-operated Ca2+ entry cause immunodeficiency, myopathy, and ectodermal dysplasia","volume":"124","author":"Rosenwasser","year":"2010","journal-title":"Fac. Opin. Post Publ. Peer Rev. Biomed. Lit."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1093\/oxfordjournals.jbchem.a021780","article-title":"2APB, 2-Aminoethoxydiphenyl Borate, a Membrane-Penetrable Modulator of Ins(1,4,5)P3-Induced Ca2+ Release","volume":"122","author":"Maruyama","year":"1997","journal-title":"J. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"21617","DOI":"10.1074\/jbc.M202549200","article-title":"Comparison of human TRPC3 channels in receptor-activated and store-operated modes. Differential sensitivity to channel blockers suggests fundamental differences in channel composition","volume":"277","author":"Trebak","year":"2002","journal-title":"J Biol Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8618","DOI":"10.1111\/j.1476-5381.1994.tb17072.x","article-title":"Inhibition by SK&F 96365 of Ca2+ current, IL-2 production and activation in T lymphocytes","volume":"113","author":"Chung","year":"1994","journal-title":"Br. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"817","DOI":"10.4155\/fmc-2016-0024","article-title":"Store-operated CRAC channel inhibitors: Opportunities and challenges","volume":"8","author":"Tian","year":"2016","journal-title":"Futur. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0143-4160(86)90026-6","article-title":"A model for receptor-regulated calcium entry","volume":"7","author":"Putney","year":"1986","journal-title":"Cell Calcium"},{"key":"ref_25","first-page":"902","article-title":"STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane","volume":"437","author":"Zhang","year":"2005","journal-title":"Nat. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.clim.2010.01.011","article-title":"Immunodeficiency due to mutations in ORAI1 and STIM1","volume":"135","author":"Feske","year":"2010","journal-title":"Clin. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1111\/nyas.12938","article-title":"Diseases caused by mutations inORAI1andSTIM1","volume":"1356","author":"Lacruz","year":"2015","journal-title":"Ann. New York Acad. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"14714","DOI":"10.1038\/ncomms14714","article-title":"ORAI2 modulates store-operated calcium entry and T cell-mediated immunity","volume":"8","author":"Vaeth","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"19173","DOI":"10.1074\/jbc.M110.102582","article-title":"A novel native store-operated calcium channel encoded by Orai3:Selective requirement of Orai3 versus Orai1 in estrogen receptor positive versus estrogen receptor negative breast cancer cells","volume":"285","author":"Motiani","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_30","first-page":"230","article-title":"Orai1 is an essential pore subunit of the CRAC channel","volume":"443","author":"Prakriya","year":"2006","journal-title":"Nat. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"E3539","DOI":"10.1073\/pnas.1218247109","article-title":"Orai-STIM-mediated Ca2+ release from secretory granules revealed by a targeted Ca2+ and pH probe","volume":"109","author":"Dickson","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Varadarajan, S., Tanaka, K., Smalley, J.L., Bampton, E.T.W., Pellecchia, M., Dinsdale, D., Willars, G.B., and Cohen, G.M. (2013). Endoplasmic Reticulum Membrane Reorganization Is Regulated by Ionic Homeostasis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0056603"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.bbrc.2014.07.060","article-title":"Orai-2 is localized on secretory granules and regulates antigen-evoked Ca2+ mobilization and exocytosis in mast cells","volume":"451","author":"Ikeya","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1126\/science.1228757","article-title":"Crystal structure of the calcium release-activated calcium channel Orai","volume":"338","author":"Hou","year":"2012","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4896","DOI":"10.1073\/pnas.1001169107","article-title":"Pore architecture of the ORAI1 store-operated calcium channel","volume":"107","author":"Zhou","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1016\/j.bpj.2016.09.020","article-title":"Functional Analysis of Orai1 Concatemers Supports a Hexameric Stoichiometry for the CRAC Channel","volume":"111","author":"Yen","year":"2016","journal-title":"Biophys. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"25764","DOI":"10.1074\/jbc.M116.758813","article-title":"The Orai1 Store-operated Calcium Channel Functions as a Hexamer","volume":"291","author":"Cai","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Dellis, O., Mercier, P., and Chomienne, C. (2011). The boron-oxygen core of borinate esters is responsible for the store-operated calcium entry potentiation ability. BMC Pharmacol., 11.","DOI":"10.1186\/1471-2210-11-1"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2903","DOI":"10.1113\/jphysiol.2009.170662","article-title":"Properties of Orai1 mediated store-operated current depend on the expression levels of STIM1 and Orai1 proteins","volume":"587","author":"Scrimgeour","year":"2009","journal-title":"J. Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1073\/pnas.0712288105","article-title":"Functional interactions among Orai1, TRPCs, and STIM1 suggest a STIM-regulated heteromeric Orai\/TRPC model for SOCE\/Icrac channels","volume":"105","author":"Liao","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1007\/s00424-018-2165-5","article-title":"Calcium store refilling and STIM activation in STIM- and Orai-deficient cell lines","volume":"470","author":"Zheng","year":"2018","journal-title":"Pfl\u00fcgers Archiv. Eur. J. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/0896-6273(90)90029-F","article-title":"Expressed cerebellar-type inositol 1,4,5-trisphosphate receptor, P400, has calcium release activity in a fibroblast L cell line","volume":"5","author":"Miyawaki","year":"1990","journal-title":"Neuron"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3440","DOI":"10.1016\/S0021-9258(19)83641-4","article-title":"A new generation of Ca2+ indicators with greatly improved fluorescence properties","volume":"260","author":"Grynkiewicz","year":"1985","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4466","DOI":"10.18632\/oncotarget.27063","article-title":"Improvement of the rituximab\u2013induced cell death by potentiation of the store-operated calcium entry in mantle cell lymphoma cell lines","volume":"10","author":"Doignon","year":"2019","journal-title":"Oncotarget"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6044","DOI":"10.1074\/jbc.M111831200","article-title":"Inhibition of the Calcium Release-activated Calcium (CRAC) Current in Jurkat T Cells by the HIV-1 Envelope Protein gp160","volume":"277","author":"Dellis","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/0003-2697(92)90183-8","article-title":"Bound and determined: A computer program for making buffers of defined ion concentrations","volume":"201","author":"Brooks","year":"1992","journal-title":"Anal. Biochem."},{"key":"ref_47","first-page":"289","article-title":"Measurement of intracellular Ca2+ release in permeabilized cells using 45Ca2+","volume":"2014","author":"Luyten","year":"2014","journal-title":"Cold Spring Harb. Protoc."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/978-94-007-2888-2_11","article-title":"Inositol 1,4,5-Trisphosphate and Its Receptors","volume":"740","author":"Parys","year":"2012","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1055\/s-0036-1588345","article-title":"Borinic Acids via Direct Arylation of Amine\u2013Borane Complexes: An Air- and Water-Stable Boron Source","volume":"49","author":"Pinet","year":"2016","journal-title":"Synthesis"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.bbrc.2006.10.174","article-title":"2-Aminoethyl diphenylborinate analogues: Selective inhibition for store-operated Ca2+ entry","volume":"352","author":"Zhou","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_51","unstructured":"Ohane, K., and Hayase, Y. (2002). Nematicide for Plant Containing Organoboron Compound. (JP2002322007A)."},{"key":"ref_52","unstructured":"Mikoshiba, K., Iwasaki, H., Maruyama, T., and Hamano, S.-I. (2003). Intracellular Calcium Concentration Increase Inhibitors. (WO2003033002A1)."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.bbrc.2013.08.102","article-title":"2-Aminoethyl diphenylborinate (2-APB) analogues: Regulation of Ca2+ signaling","volume":"441","author":"Ozaki","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/24\/9777\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:48:09Z","timestamp":1760179689000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/24\/9777"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,21]]},"references-count":53,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["ijms21249777"],"URL":"https:\/\/doi.org\/10.3390\/ijms21249777","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2020,12,21]]}}}