New mitochondrial KV1.3 conjugates are potent and specific inducers of apoptosis in cancer models

Mitochondrial K_V1.3 channels (mitoK_V1.3) have emerged as promising targets for cancer therapy due to their role in regulating apoptosis, independent of upstream signalling pathways and Bcl-2 family protein levels. Here, we present a new non-psoralene K_v1.3 mitochondria-targeted conjugates. These conjugates, particularly cis-8 and cis-9, exhibit nanomolar affinity and high selectivity for K_V1.3 while effectively inducing apoptosis in tumor cells. Unlike their parent K_V1.3 inhibitors, which lack cytotoxicity, the mitoK_V1.3 conjugates induce rapid mitochondrial depolarization, and caspase-3/7 activation, culminating in dose-dependent tumor cell death in both 2D and 3D models. Mechanistically, cis-8 and cis-9 disrupt mitochondrial membrane potential and selectively target cancer cells, sparing normal cells at lower concentrations. Notably, K_V1.3 knockout models confirmed the dependence of cytotoxicity on mitoK_V1.3 inhibition. The conjugates demonstrated robust antitumor activity in murine pancreatic intraepithelial neoplasia (PanIN)-derived organoids, with preferential action over normal pancreatic organoids, highlighting their tumor selectivity. Importantly, safety assessments showed no significant DNA damage or chromosomal aberrations at non-cytotoxic doses. This study introduces a new structural class of mitochondria-targeted K_V1.3 inhibitors with enhanced solubility compared to psoralen-based analogues. The unique mechanism of action, characterized by rapid depolarization and moderate ROS dependence, underscores their potential as selective anticancer agents. These findings warrant further investigation into in vivo efficacy and potential synergy with existing therapies.