{rfName}
Pr

Indexed in

License and Use

Icono OpenAccess

Citations

2

Altmetrics

Share

June 2, 2025
Publications
>
Article
Sí

Prospective evaluation of CYP19A1-mediated aromatase inhibitors for ER+ breast cancers by ultra-high performance liquid chromatography tandem mass spectrometry supported by in silico methods

Publicated to: Results in Chemistry. 16 102355- - 2025-07-01 16(), DOI: 10.1016/j.rechem.2025.102355

Authors:

Gumede, NJ; Bisetty, K; Escuder-Gilabert, L; Medina-Hernandez, MJ; Sagrado, S
[+]

Affiliations

Durban Univ Technol, Dept Chem, POB 1334, ZA-4000 Durban, South Africa - Author
Univ Valencia, Fac Farm, Dept Quim Analit, Avda Vicent Andres Estelles,S-N, E-46100 Burjassot, Valencia, Spain - Author
Univ Valencia, Univ Politecn Valencia, Inst Interuniv Invest Reconocimiento Mol & Desarro, Avda Vicent Andres Estelles,S-N, E-46100 Burjassot, Valencia, Spain - Author
Walter Sisulu Univ, Fac Nat Sci, Dept Chem & Phys Sci, Private Bag X01, ZA-5011 Mthatha, South Africa - Author
See more

Abstract

Human aromatase (CYP19A1) is a membrane-associated microsomal cytochrome P450 enzyme that is responsible for facilitating the conversion of androgens into estrogens. Aromatase inhibitors (AIs) are widely utilized in the management of breast cancer, and the CYP19A1 aromatase is acknowledged as a validated target for therapeutic intervention in estrogen receptor positive (ER+) breast cancer. In this study, we assessed the efficacy of 13 compounds in inhibiting CYP19A1-mediated aromatization using ultra-high-performance liquid chromatography tandem mass spectroscopy (UHPLC-MS/MS). Compound 12 emerged as the most potent inhibitor, with an IC50 of 3.5 mu M. A selectivity assay involving the CYP17A1 enzyme and five major CYP450 isoforms further demonstrated that compound 12 exhibited significant selectivity for CYP19A1. This finding suggests that compound 12 could be considered a potential lead for subsequent hit-to-lead optimization, offering a novel scaffold compared with other compounds currently in various stages of clinical development. Additionally, molecular docking analyses were conducted on the compound 12-CYP19A1 complex, both with and without the imposition of metal constraints. Docking with metal constraints validated the binding network, revealing strong hydrogen bonds with ASP309, MET374, and a metal ligand coordination between the heme iron atom of CYP19A1 and compound 12. We have performed Structure Activity Relationship (SAR) studies on compound 12, however the results cannot be disclosed for now since they are patent pending. Thus, the current work can be considered as a prospective study.
[+]

Keywords

Accurate dockingBindingBreast cancerCytochrome-p450DesignEr + breast canceFlexibilityGenerationGlideMechanismPredictioProtein

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Results in Chemistry due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2025, it was in position 84/239, thus managing to position itself as a Q2 (Segundo Cuartil), in the category Chemistry, Multidisciplinary. Notably, the journal is positioned en el Cuartil Q2 para la agencia Scopus (SJR) en la categoría Chemistry (Miscellaneous).

[+]

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2026-04-03:

  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 3 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

    It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

    • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
    [+]

    Leadership analysis of institutional authors

    This work has been carried out with international collaboration, specifically with researchers from: South African Republic.

    There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: Last Author (Sagrado, S).

    [+]

    Awards linked to the item

    This research work was supported financially in part by the National Research Foundation of South Africa under the Black Academics advancement programme (UID: 112151) . This work was also made possible through funding by the Research Capacity Development Initiative-South African Medical Research Council (RCDI-SAMRC) . The content hereof is the sole responsibility of the authors and does not necessarily represent the official views of NRF and SAMRC. The authors would like to acknowledge the Centre for High Performance Computing for allowing access to their resources for molecular modeling. Authors would also like to thank Xenogesis and Enamine Ltd. for performing bioanalytical experiments, custom synthesis of the compounds, as outsourced services, respectively.
    [+]