Estrogen deficiency derived from inhibition of estrogen biosynthesis is a typical condition of postmenopausal women and breast cancer (BCs) patients undergoing antihormone therapy. The ensuing increase in aldosterone levels is considered to be the major cause for cardiovascular diseases (CVDs) affecting these patients. Since estrogen biosynthesis is regulated by aromatase (CYP19A1), and aldosterone biosynthesis is modulated by aldosterone synthase (CYP11B2), a dual inhibitor would allow the treatment of BC while reducing the cardiovascular risks typical of these patients. Moreover, this strategy would help overcome some of the disadvantages often observed in single-target or combination therapies. Following an in-depth analysis of a library of synthesized benzylimidazole derivatives, compound X21 was found to be a potent and selective dual inhibitor of aromatase and aldosterone synthase, with IC50 values of 2.3 and 29 nM, respectively. Remarkably, the compound showed high selectivity with respect to 11β-hydroxylase (CYP11B1), as well as CYP3A4 and CYP1A2. When tested in cells, X21 showed potent antiproliferative activity against BC cell lines, particularly against the ER+ MCF-7 cells (IC50 of 0.26 ± 0.03 μM at 72 h), and a remarkable pro-apoptotic effect. In addition, the compound significantly inhibited mTOR phosphorylation at its IC50 concentration, thereby negatively modulating the PI3K/Akt/mTOR axis, which represents an escape for the dependency from ER signaling in BC cells. The compound was further investigated for cytotoxicity on normal cells and potential cardiotoxicity against hERG and Nav1.5 ion channels, demonstrating a safe biological profile. Overall, these assays demonstrated that the compound is potent and safe, thus constituting an excellent candidate for further evaluation.

Discovery of a Potent Dual Inhibitor of Aromatase and Aldosterone Synthase / Tinivella, A.; Banchi, M.; Gambacorta, G.; Borghi, F.; Orlandi, P.; Baxendale, I. R.; Di Paolo, A.; Bocci, G.; Pinzi, L.; Rastelli, G.. - In: ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE. - ISSN 2575-9108. - 6:12(2023), pp. 1870-1883. [10.1021/acsptsci.3c00183]

Discovery of a Potent Dual Inhibitor of Aromatase and Aldosterone Synthase

Tinivella A.;Banchi M.;Orlandi P.;Di Paolo A.;Bocci G.;Pinzi L.;Rastelli G.
2023

Abstract

Estrogen deficiency derived from inhibition of estrogen biosynthesis is a typical condition of postmenopausal women and breast cancer (BCs) patients undergoing antihormone therapy. The ensuing increase in aldosterone levels is considered to be the major cause for cardiovascular diseases (CVDs) affecting these patients. Since estrogen biosynthesis is regulated by aromatase (CYP19A1), and aldosterone biosynthesis is modulated by aldosterone synthase (CYP11B2), a dual inhibitor would allow the treatment of BC while reducing the cardiovascular risks typical of these patients. Moreover, this strategy would help overcome some of the disadvantages often observed in single-target or combination therapies. Following an in-depth analysis of a library of synthesized benzylimidazole derivatives, compound X21 was found to be a potent and selective dual inhibitor of aromatase and aldosterone synthase, with IC50 values of 2.3 and 29 nM, respectively. Remarkably, the compound showed high selectivity with respect to 11β-hydroxylase (CYP11B1), as well as CYP3A4 and CYP1A2. When tested in cells, X21 showed potent antiproliferative activity against BC cell lines, particularly against the ER+ MCF-7 cells (IC50 of 0.26 ± 0.03 μM at 72 h), and a remarkable pro-apoptotic effect. In addition, the compound significantly inhibited mTOR phosphorylation at its IC50 concentration, thereby negatively modulating the PI3K/Akt/mTOR axis, which represents an escape for the dependency from ER signaling in BC cells. The compound was further investigated for cytotoxicity on normal cells and potential cardiotoxicity against hERG and Nav1.5 ion channels, demonstrating a safe biological profile. Overall, these assays demonstrated that the compound is potent and safe, thus constituting an excellent candidate for further evaluation.
2023
6
12
1870
1883
Discovery of a Potent Dual Inhibitor of Aromatase and Aldosterone Synthase / Tinivella, A.; Banchi, M.; Gambacorta, G.; Borghi, F.; Orlandi, P.; Baxendale, I. R.; Di Paolo, A.; Bocci, G.; Pinzi, L.; Rastelli, G.. - In: ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE. - ISSN 2575-9108. - 6:12(2023), pp. 1870-1883. [10.1021/acsptsci.3c00183]
Tinivella, A.; Banchi, M.; Gambacorta, G.; Borghi, F.; Orlandi, P.; Baxendale, I. R.; Di Paolo, A.; Bocci, G.; Pinzi, L.; Rastelli, G.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1340313
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