20.500.12556/RUL-140829 New diarylamine KV10.1 inhibitors and their anticancer potential Expression of the voltage-gated potassium channel KV10.1 (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 KV10.1 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 KV10.1 and hERG were investigated using whole-cell patch-clamp experiments. We obtained two new optimised KV10.1 inhibitors, 17a and 18b, with improved nanomolar IC50 values of 568 nM and 214 nM, respectively. Compound 17a exhibited better ratio between IC50 values for hEAG1 and hERG than previously published diarylamine inhibitors. Compounds 17a and 18b moderately inhibited the growth of the KV10.1-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 KV10.1 inhibitors remains the selectivity toward the hERG channel, which needs to be addressed with targeted drug design strategies in the future. KV10.1 ion channels hERG SAR antiproliferative activity KV10.1 ionski kanali hERG SAR antiproliferativno delovanje true false true Angleški jezik Slovenski jezik Članek v reviji 2022-09-19 10:45:03 2022-09-19 10:45:06 2022-09-20 04:05:01 0000-00-00 00:00:00 2022 0 0 27 str. iss. 8, art. 1963 Vol. 14 2022 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 577.352 1999-4923 10.3390/pharmaceutics14091963 121841667 pharmaceutics-14-01963.pdf pharmaceutics-14-01963.pdf 1 BEBE41AD6E2A86705D89FCDD39D90418 096def545473dcdc32eeebad0ba3e11fe0c11eeccd89530fbaff391630968331 a3854a76-37f7-11ed-92af-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=161632 https://www.mdpi.com/1999-4923/14/9/1963 1 4a4b2651-37f7-11ed-92af-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=161631 Fakulteta za farmacijo 0 0 0