New bioisosteric sulphur-containing choline kinase inhibitors with a tracked mode of action Luque Navarro, Pilar María Carrasco Jiménez, María Paz Goracci, Laura Paredes Martínez, José Manuel Espinar Barranco, Laura Valverde Pozo, Javier Torretta, Archimede Parisini, Emilio Mariotto, Elena Marchioro, Chiara Laso, Alejandro Marco De La Calle, Carmen Viola, Giampietro Lanari, Daniela López Cara, Luisa Carlota Antitumoral drug Choline kinase inhibition Bioisosterism Environmental synthesis This research was funded by Convocatoria 2019 Proyectos de I + D + i − RTI Tipo B “Ministerio de Innovación y Ciencia” [grant number PID2019-109294RB-I00] and “Convocatoria 2020 Proyectos I + D + i del Programa Operativo FEDER 2020”, [grant number B-CTS-216-UGR20]. E.P. thanks the ERDF project BioDrug [No. 1.1.1.5/19/A/004] and the Latvian Council of Science [grant number lzp-2020/2-0013] for financial support. Since the identification of human choline kinase as a protein target against cancer progression, many compounds have been designed to inhibit its function and reduce the biosynthesis of phosphatidylcholine. Herein, we propose a series of bioisosteric inhibitors that are based on the introduction of sulphur and feature improved activity and lipophilic/hydrophilic balance. The evaluation of the inhibitory and of the antiproliferative properties of the PL (dithioethane) and FP (disulphide) libraries led to the identification of PL 48, PL 55 and PL 69 as the most active compounds of the series. Docking analysis using FLAP suggests that for hits to leads, binding mostly involves an interaction with the Mg2+ cofactor, or its destabilization. The most active compounds of the two series are capable of inducing apoptosis following the mitochondrial pathway and to significantly reduce the expression of anti-apoptotic proteins such as the Mcl-1. The fluorescence properties of the compounds of the PL library allowed the tracking of their mode of action, while PAINS (Pan Assays Interference Structures) filtration databases suggest the lack of any unspecific biological response. 2025-02-03T11:02:54Z 2025-02-03T11:02:54Z 2023 journal article Published version: Pilar M. Luque-Navarro et al. New bioisosteric sulphur-containing choline kinase inhibitors with a tracked mode of action. European Journal of Medicinal Chemistry 2023, 246, 115002; doi: 10.1016/j.ejmech.2022.115003 https://hdl.handle.net/10481/101891 10.1016/j.ejmech.2022.115003 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Elsevier