Synthesis and Characterization of Store-Operated Calcium Entry Inhibitors Active in the Submicromolar Range
The store-operated calcium entry, better known as SOCE, forms the main Ca<sup>2+</sup> 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 l...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/24/9777 |
| _version_ | 1797543935388680192 |
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| author | Camille Le Guilcher Tomas Luyten Jan B. Parys Mathieu Pucheault Olivier Dellis |
| author_facet | Camille Le Guilcher Tomas Luyten Jan B. Parys Mathieu Pucheault Olivier Dellis |
| author_sort | Camille Le Guilcher |
| collection | DOAJ |
| description | The store-operated calcium entry, better known as SOCE, forms the main Ca<sup>2+</sup> 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 <i>K</i><sub>i</sub> ≈ 75 nM. Furthermore, below 1 µM, P11 was devoid of any inhibitory activity on the two other main cellular targets of 2-APB, the IP<sub>3</sub> 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. |
| first_indexed | 2024-03-10T13:52:32Z |
| format | Article |
| id | doaj.art-a858a2f39ebb499d9d9e481c7fcaf014 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T13:52:32Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a858a2f39ebb499d9d9e481c7fcaf0142023-11-21T01:59:07ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-12-012124977710.3390/ijms21249777Synthesis and Characterization of Store-Operated Calcium Entry Inhibitors Active in the Submicromolar RangeCamille Le Guilcher0Tomas Luyten1Jan B. Parys2Mathieu Pucheault3Olivier Dellis4Physiopathogénèse et Traitements des Maladies du Foie, Université Paris-Saclay, Rue des Adeles, 91405 Orsay, FranceLaboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut, B-3000 Leuven, BelgiumLaboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut, B-3000 Leuven, BelgiumInstitute of Molecular Science, CNRS, Université de Bordeaux, 33400 Talence, FrancePhysiopathogénèse et Traitements des Maladies du Foie, Université Paris-Saclay, Rue des Adeles, 91405 Orsay, FranceThe store-operated calcium entry, better known as SOCE, forms the main Ca<sup>2+</sup> 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 <i>K</i><sub>i</sub> ≈ 75 nM. Furthermore, below 1 µM, P11 was devoid of any inhibitory activity on the two other main cellular targets of 2-APB, the IP<sub>3</sub> 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.https://www.mdpi.com/1422-0067/21/24/9777store-operated calcium entryinhibitorsynthesisapoptosis |
| spellingShingle | Camille Le Guilcher Tomas Luyten Jan B. Parys Mathieu Pucheault Olivier Dellis Synthesis and Characterization of Store-Operated Calcium Entry Inhibitors Active in the Submicromolar Range International Journal of Molecular Sciences store-operated calcium entry inhibitor synthesis apoptosis |
| title | Synthesis and Characterization of Store-Operated Calcium Entry Inhibitors Active in the Submicromolar Range |
| title_full | Synthesis and Characterization of Store-Operated Calcium Entry Inhibitors Active in the Submicromolar Range |
| title_fullStr | Synthesis and Characterization of Store-Operated Calcium Entry Inhibitors Active in the Submicromolar Range |
| title_full_unstemmed | Synthesis and Characterization of Store-Operated Calcium Entry Inhibitors Active in the Submicromolar Range |
| title_short | Synthesis and Characterization of Store-Operated Calcium Entry Inhibitors Active in the Submicromolar Range |
| title_sort | synthesis and characterization of store operated calcium entry inhibitors active in the submicromolar range |
| topic | store-operated calcium entry inhibitor synthesis apoptosis |
| url | https://www.mdpi.com/1422-0067/21/24/9777 |
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