Design of New Potent and Selective Thiophene-Based KV1.3 Inhibitors and Their Potential for Anticancer Activity

• Published in: Cancers Vol. 14; no. 11; p. 2595
• Main Authors: Gubič, Špela, Hendrickx, Louise, Shi, Xiaoyi, Toplak, Žan, Možina, Štefan, Theemsche, Kenny, Pinheiro-Junior, Ernesto, Peigneur, Steve, Labro, Alain, Pardo, Luis, Tytgat, Jan, Tomašič, Tihomir, Mašič, Lucija
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 24.05.2022; MDPI
• Subjects: Antitumor activity; Antitumor agents; Apoptosis; Binding sites; Cancer; Cell culture; Cell proliferation; Drug discovery; Laboratory animals; Oocytes; Plasmids; Potassium; Potassium channels (voltage-gated); Software; Spheroids; Statistical analysis; Tumor markers; United States > US; Germany
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers14112595

The voltage-gated potassium channel KV1.3 has been recognized as a tumor marker and represents a promising new target for the discovery of new anticancer drugs. We designed a novel structural class of KV1.3 inhibitors through structural optimization of benzamide-based hit compounds and structure-activity relationship studies. The potency and selectivity of the new KV1.3 inhibitors were investigated using whole-cell patch- and voltage-clamp experiments. 2D and 3D cell models were used to determine antiproliferative activity. Structural optimization resulted in the most potent and selective KV1.3 inhibitor 44 in the series with an IC50 value of 470 nM in oocytes and 950 nM in Ltk− cells. KV1.3 inhibitor 4 induced significant apoptosis in Colo-357 spheroids, while 14, 37, 43, and 44 significantly inhibited Panc-1 proliferation.