New Diarylamine K V 10.1 Inhibitors and Their Anticancer Potential.

Autor: Gubič Š; Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia., Toplak Ž; Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia., Shi X; AG Oncophysiology, Max-Planck Institute for Experimental Medicine, Hermann-Rein-Str. 3, 37075 Göttingen, Germany., Dernovšek J; Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia., Hendrickx LA; Toxicology and Pharmacology, Campus Gasthuisberg, University of Leuven, Onderwijs en Navorsing 2, Herestraat 49, 3000 Leuven, Belgium., Pinheiro-Junior EL; Toxicology and Pharmacology, Campus Gasthuisberg, University of Leuven, Onderwijs en Navorsing 2, Herestraat 49, 3000 Leuven, Belgium., Peigneur S; Toxicology and Pharmacology, Campus Gasthuisberg, University of Leuven, Onderwijs en Navorsing 2, Herestraat 49, 3000 Leuven, Belgium., Tytgat J; Toxicology and Pharmacology, Campus Gasthuisberg, University of Leuven, Onderwijs en Navorsing 2, Herestraat 49, 3000 Leuven, Belgium., Pardo LA; AG Oncophysiology, Max-Planck Institute for Experimental Medicine, Hermann-Rein-Str. 3, 37075 Göttingen, Germany., Peterlin Mašič L; Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia., Tomašič T; Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
Jazyk: angličtina
Zdroj: Pharmaceutics [Pharmaceutics] 2022 Sep 17; Vol. 14 (9). Date of Electronic Publication: 2022 Sep 17.
DOI: 10.3390/pharmaceutics14091963
Abstrakt: Expression of the voltage-gated potassium channel K V 10.1 (Eag1) has been detected in over 70% of human cancers, making the channel a promising new target for new anticancer drug discovery. A new structural class of K V 10.1 inhibitors was prepared by structural optimisation and exploration of the structure-activity relationship of the previously published hit compound ZVS-08 ( 1 ) and its optimised analogue 2 . The potency and selectivity of the new inhibitors between K V 10.1 and hERG were investigated using whole-cell patch-clamp experiments. We obtained two new optimised K V 10.1 inhibitors, 17a and 18b , with improved nanomolar IC 50 values of 568 nM and 214 nM, respectively. Compound 17a exhibited better ratio between IC 50 values for hEAG1 and hERG than previously published diarylamine inhibitors. Compounds 17a and 18b moderately inhibited the growth of the K V 10.1-expressing cell line MCF-7 in two independent assays. In addition, 17a and 18b also inhibited the growth of hERG-expressing Panc-1 cells with higher potency compared with MCF-7 cells. The main obstacle for newly developed diarylamine K V 10.1 inhibitors remains the selectivity toward the hERG channel, which needs to be addressed with targeted drug design strategies in the future.
Databáze: MEDLINE
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