Discovery of a Potent Dual Inhibitor of Aromatase and Aldosterone Synthase.

Tinivella, Annachiara; Banchi, Marta; Gambacorta, Guido; Borghi, Federica; Orlandi, Paola; Baxendale, Ian R; Di Paolo, Antonello; Bocci, Guido; Pinzi, Luca; Rastelli, Giulio

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 was found to be a potent and selective dual inhibitor of aromatase and aldosterone synthase, with IC 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, showed potent antiproliferative activity against BC cell lines, particularly against the ER+ MCF-7 cells (IC 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 IC 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 ERG 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. [Abstract copyright: © 2023 The Authors. Published by American Chemical Society.]

Citation

Tinivella, A., Banchi, M., Gambacorta, G., Borghi, F., Orlandi, P., Baxendale, I. R., …Rastelli, G. (2023). Discovery of a Potent Dual Inhibitor of Aromatase and Aldosterone Synthase. ACS pharmacology & translational science, 6(12), 1870-1883. https://doi.org/10.1021/acsptsci.3c00183

• Journal Article Type: Article
• Acceptance Date: Nov 6, 2023
• Online Publication Date: Nov 23, 2023
• Publication Date: Dec 8, 2023
• Deposit Date: Jan 18, 2024
• Publicly Available Date: Jan 18, 2024
• Journal: ACS pharmacology & translational science
• Print ISSN: 2575-9108
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 6
• Issue: 12
• Pages: 1870-1883
• DOI: https://doi.org/10.1021/acsptsci.3c00183
• Public URL: https://durham-repository.worktribe.com/output/2075716