Directed C–H activation of 13α-estrone : a pathway to promising AKR1C inhibitors via docking and biological studies

Mernyák, Erzsébet (author), Gjorgoska, Marija (author), Sinreih, Maša (author), Kotnik, Aljaž (author), Zanoškar, Zala (author), Godec, Ajda (author), Jukič, Marko (author), Bren, Urban (author), Ignácz, Rebeka (author), Szőri, Kornél (author), Kele, Zoltán (author), Hunyadi, Attila (author), Lanišnik-Rižner, Tea (author)

The aldo-keto reductase isoenzymes AKR1C1–3 regulate local steroid hormone availability through the interconversion of active and inactive ligands, thereby modulating prereceptor signaling. This regulatory mechanism has been implicated in the progression of hormone-dependent malignancies, highlighting AKR1C enzymes as attractive therapeutic targets for endocrine-related cancers. The AKR1C family is also known to mediate resistance to multiple classes of chemotherapeutic agents through various mechanisms. Inhibition of AKR1C enzymes may therefore potentiate the cytotoxic effects of chemotherapeutic agents. Building on our recent work describing potent A-ring halogenated 13a-estrone-based AKR1C inhibitors, we now report further structural modifications via directed C–H activation on the same scaffold. Following the introduction of a directing group, hydroxylation or acetoxylation was performed at the C-2 position. The newly synthesized compounds were evaluated against recombinant AKR1C1–3 enzymes. Notably, two new derivatives (4 and 6a) exhibited low micromolar, isoform-selective inhibitory activity against AKR1C2. Moreover, using in silico molecular docking, we postulated the binding conformations of active pyridyloxy derivative (6a), triazinyl derivative (7) and aryl carbamate (4) within the AKR1C2 binding site, with all of them showing key interactions with Trp86, Val128, Ile129 and Trp227. The AKR1C2 inhibitors identified in this study represent promising starting points for the development of novel therapeutic agents, limiting metastatic dissemination, particularly in certain aggressive tumor types. Given that AKR1C1–3 isoenzymes often catalyze overlapping biochemical transformations, inhibition of one member may be compensated by another. Thus, while selective AKR1C inhibitors remain valuable, the development of pan-inhibitors also represents a promising therapeutic strategy.

• Language: English
• Keywords: local steroid hormone, AKR1C enzymes, inhibitors
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2026
• Number of pages: Str. 11506-11520
• Numbering: Vol. 16, iss. 13
• PID: 20.500.12556/RUL-184591
• UDC: 543.2/.9
• ISSN on article: 2046-2069
• DOI: 10.1039/D5RA08903D
• COBISS.SI-ID: 271593475
• Publication date in RUL: 10.07.2026

Record is a part of a journal

• Title: RSC advances
• Publisher: RSC Publishing
• ISSN: 2046-2069
• COBISS.SI-ID: 2513252

Licences

• License: CC BY-NC 3.0, Creative Commons Attribution-NonCommercial 3.0 Unported
• Link: http://creativecommons.org/licenses/by-nc/3.0/
• Description: You are free to reproduce and redistribute the material in any medium or format. You are free to remix, transform, and build upon the material. You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. You may not use the material for commercial purposes. You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.

Secondary language

• Language: Slovenian
• Keywords: lokalni steroidni hormoni, AKR1C encimi, inhibitorji