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| Home > Articles > Published articles > Design and synthesis of a novel non peptide CN-NFATc signaling inhibitor for tumor suppression in triple negative breast cancer |
| Home > Articles > Published articles > Design and synthesis of a novel non peptide CN-NFATc signaling inhibitor for tumor suppression in triple negative breast cancer |
(Universitat Autònoma de Barcelona. Departament de Química) (Universitat Autònoma de Barcelona. Departament de Química) (Universitat Autònoma de Barcelona. Departament de Química) (Universitat Autònoma de Barcelona. Departament de Química)
| Date: | 2022 |
| Abstract: | The Ca2/calmodulin-mediated phosphatase activity of calcineurin (CN) integrates calcium-mediated signaling with gene expression programs involved in the control of essential cellular processes in health and disease, such as the immune response and the pathogenesis of cancer progression and metastasis. In addition, CN is the target of the immunosuppressive drugs cyclosporine A (CsA) and FK-506 which are the cornerstone of immunosuppressant therapy. Unfortunately, long-term administration of these drugs results in severe side effects. Herein, we describe the design, synthesis and evaluation of new synthetic compounds that are capable of inhibiting NFATc activity in a dose-dependent manner, without interfering on CN phosphatase activity. These compounds were designed using the structure-based pharmacophore model of a peptide-derived PxIxIT sequence binding to calcineurin A subunit. Moreover, these compounds inhibit NFATc-dependent cytokine gene expression, secretion and proliferation of human T CD4 cells. More importantly, compound 5a reduces tumor weight and shows a tendency to reduce tumor angiogenesis in an orthotopic immunocompetent mouse model of triple negative breast cancer, suggesting that 5a has tumor suppressor activity. These findings validate compound 5a as an agent with therapeutic activity against CN-NFATc and highlight its potential as a tool for drug development with therapeutic purposes. |
| Grants: | Ministerio de Economía y Competitividad SAF2015-66365 Ministerio de Economía y Competitividad RTC-2015-3381-1 Ministerio de Economía y Competitividad CTQ2016-75363-R Agencia Estatal de Investigación PID2019-106403RB-I00 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014/SGR-541 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-191 |
| Note: | Altres ajuts: acords transformatius de la UAB |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Subject: | Docking-based design ; Druggability evaluation ; SAR exploration ; Calcineurin ; NFAT signaling Inhibitor ; Triple negative breast cancer ; PxIxIT |
| Published in: | European Journal of Medicinal Chemistry, Vol. 238 (August 2022) , art. 114514, ISSN 1768-3254 |
