Abstract 7142: Optimizing estradiol dimers through linker design: Enhancing anticancer efficacy by targeting microtubule dynamics

Abstract

Abstract We investigated the development and anticancer efficacy of novel estradiol dimers (ED), targeting the dynamics of microtubules—an essential factor in effective cancer therapy. Employing copper-catalyzed azide-alkyne cycloaddition (CuAAC), two distinct series of ED variants were synthesized. The initial series included thirteen dimers, derived from 17α-ethinyl estradiol, incorporating varied five-atom linkers with central carbon, nitrogen, or oxygen atoms, and, in some instances, modified with benzyl groups containing hydroxy or methoxy substituents. These dimers were evaluated for their cytotoxic properties and impact on the cell cycle, revealing certain structures with substantial efficacy, compared with the original ED. The subsequent series, encompassing twelve variants, concentrated on structural alterations within the aromatic bridges linking the estradiol units. In this series, linkers of simpler composition and fewer substituents demonstrated increased selectivity and potency against cancer cell lines, particularly ED3 and ED5, which exhibited cytotoxicity levels comparable to established tubulin inhibitors. Both dimers series showed the ability to disrupt microtubule assembly and mitotic processes, confirmed through cell-based evaluations and in vitro tubulin assembly assays. Complementing these results, in silico modelling and binding free energy calculations exhibited a strong correlation with the demonstrated biological activities, especially in terms of binding affinity to the colchicine site. Collectively, these findings highlight the promise of estradiol dimers as potential anticancer agents and emphasize the critical role of linker structures in enhancing their biological effectiveness. Work was supported by the Ministry of Education, Youth and Sports of the Czech Republic through infrastructural projects (CZ-OPENSCREEN - LM2018130; EATRIS-CZ - LM2018133) and National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102) - Funded by the European Union - Next Generation EU. Citation Format: Petr Dzubak, Michal Jurášek, Jiří Řehulka, Soňa Gurská, Pavel Polishchuk, Pavel Dráber, Lukáš Huml, Pavel B. Drašar, Alexandra Ivanova, Olena Mokshyna, Lenka Hrubá, Marián Hajdúch. Optimizing estradiol dimers through linker design: Enhancing anticancer efficacy by targeting microtubule dynamics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7142.