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

Abstract

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.

Potassium channels: Novel targets for tumor diagnosis and chemoresistance

“…The specific Kv1.3 channel inhibitor clofazimine, as a membrane-permeable small molecule organic compound, can inhibit cancer cell proliferation and induce cancer cell apoptosis through the mitochondrial pathway ( 9 ). The researchers found that the Kv1.3 inhibitor tetrahydropyran inhibited PC cell proliferation and induced apoptosis ( 58 ). In vitro experiments revealed that the mitochondrial Kv1.3 inhibitors PAPTP and PCARBTP were able to promote apoptosis in multiple myeloma cell lines L-363 and RPMI-8226 ( 67 ).…”

Voltage-Gated Potassium Channels Kv1.3 in Health and Disease

“…Recently, Gubic and co-workers designed a novel structural class of small-molecule organic Kv1.3 channel inhibitors through structural optimisation of benzamide-based hit compounds and structure-activity relationship studies [30]. Structure optimisation resulted in a potent and selective Kv1.3 channel inhibitor (compound no 44) with an IC50 value of 470 nM for Kv1.3 channels expressed in Xenopus oocytes and 950 nM in Kv1.3 channel-expressing Ltk − cell line [30].…”

“…Recently, Gubic and co-workers designed a novel structural class of small-molecule organic Kv1.3 channel inhibitors through structural optimisation of benzamide-based hit compounds and structure-activity relationship studies [30]. Structure optimisation resulted in a potent and selective Kv1.3 channel inhibitor (compound no 44) with an IC50 value of 470 nM for Kv1.3 channels expressed in Xenopus oocytes and 950 nM in Kv1.3 channel-expressing Ltk − cell line [30]. Four most potent inhibitors (compounds no 14, 37, 43 and 44) significantly inhibited proliferation of Kv1.3 channel-expressing cell line Panc-1, whereas one inhibitor (hit compound no 4) induced apoptosis of Kv1.3 channel-expressing cell line Colo357 [30].…”

Correction: Gubič et al. Design of New Potent and Selective Thiophene-Based KV1.3 Inhibitors and Their Potential for Anticancer Activity. Cancers 2022, 14, 2595

“…In the original publication [1], there was a mistake in Table 3 as published. The IC 50 value determined based on Ltk cells for PAP-1 is 1000 times lower.…”

“…Table 3. Comparison of K V 1.3 IC 50 values for compounds 14, 37, 43, 44, and PAP-1 (1) obtained with HiClamp and manual voltage-clamp on Xenopus laevis oocytes (Tables 1 and 2) and with manual patch-clamp on the Ltk − cell-line.…”