New Diarylamine K_V10.1 Inhibitors and Their Anticancer Potential

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Oncology

Background:

• Voltage-gated potassium channel K_V10.1 (Eag1) is overexpressed in over 70% of human cancers.
• K_V10.1 represents a promising therapeutic target for novel anticancer drug discovery.

Purpose of the Study:

• To synthesize and optimize a new structural class of K_V10.1 inhibitors.
• To evaluate the potency and selectivity of novel inhibitors against K_V10.1 and the hERG channel.

Main Methods:

• Structure-activity relationship (SAR) studies were performed on a hit compound (ZVS-08, 1) and its analogues.
• Whole-cell patch-clamp electrophysiology was used to assess channel inhibition.
• Cell proliferation assays were conducted to evaluate the impact on cancer cell lines.

Main Results:

• Two optimized K_V10.1 inhibitors, 17a and 18b, were identified with nanomolar IC₅₀ values (568 nM and 214 nM, respectively).
• Compound 17a demonstrated improved selectivity for K_V10.1 over hERG compared to previous diarylamine inhibitors.
• Both compounds showed moderate inhibition of K_V10.1-expressing MCF-7 cells and higher potency against hERG-expressing Panc-1 cells.

Conclusions:

• Novel diarylamine K_V10.1 inhibitors with improved potency were developed.
• Selectivity over the hERG channel remains a key challenge for future drug design strategies targeting K_V10.1.