New Diarylamine K[sub.V]10.1 Inhibitors and Their Anticancer Potential

• Published in: Pharmaceutics 2022-09, Vol.14 (9)
• Main Authors: Gubič, Špela, Toplak, Žan, Shi, Xiaoyi, Dernovšek, Jaka, Hendrickx, Louise Antonia, Pinheiro-Junior, Ernesto Lopes, Peigneur, Steve, Tytgat, Jan, Pardo, Luis A, Peterlin Mašič, Lucija, Tomašič, Tihomir
• Format: Article
• Language: English
• Subjects: Cancer; Care and treatment; Dosage and administration; Potassium channel blockers
• ISSN: 1999-4923; 1999-4923
• DOI: 10.3390/pharmaceutics14091963

Expression of the voltage-gated potassium channel K[sub.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[sub.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[sub.V] 10.1 and hERG were investigated using whole-cell patch-clamp experiments. We obtained two new optimised K[sub.V] 10.1 inhibitors, 17a and 18b, with improved nanomolar IC[sub.50] values of 568 nM and 214 nM, respectively. Compound 17a exhibited better ratio between IC[sub.50] values for hEAG1 and hERG than previously published diarylamine inhibitors. Compounds 17a and 18b moderately inhibited the growth of the K[sub.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[sub.V] 10.1 inhibitors remains the selectivity toward the hERG channel, which needs to be addressed with targeted drug design strategies in the future.