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Title: Design and synthesis of a novel non peptide CN-NFATc signaling inhibitor for tumor suppression in triple negative breast cancer
Author: Sánchez Morales, Adrià
Biçer, Atilla
Panagiotopoulos, Vasilis
Crecente Garcia, Selma
Benaiges, Cristina
Bayod, Sergi
Hernández, José Luis
Busqué, Félix
Matsoukas, Minos Timotheos
Pérez Riba, Mercè
Alibés, Ramon
Keywords: Càncer de mama
Proteïnes supressores de tumors
Breast cancer
Tumor suppressor protein
Issue Date: 1-Jul-2022
Publisher: Elsevier BV
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.
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It is part of: European Journal of Medicinal Chemistry, 2022, vol. 238, p. 114514
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Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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