Voltage-gated potassium channels as therapeutic targets

Abstract

The human genome contains 40 voltage-gated potassium channels (K V ) which are involved in diverse physiological processes ranging from repolarization of neuronal or cardiac action potentials, over regulating calcium signaling and cell volume, to driving cellular proliferation and migration. K V channels offer tremendous opportunities for the development of new drugs for cancer, autoimmune diseases and metabolic, neurological and cardiovascular disorders. This review first discusses pharmacological strategies for targeting K V channels with venom peptides, antibodies and small molecules and then highlights recent progress in the preclinical and clinical development of drugs targeting K V 1.x, K V 7.x (KCNQ), K V 10.1 (EAG1) and K V 11.1 (hERG) channels.

Targeting proliferation of chronic lymphocytic leukemia (CLL) cells through KCa3.1 blockade

“…1,2 Given the importance of controlling Ca 2 þ -influx, there is growing interest in selective K þ channel blockers to suppress cell proliferation in autoimmune diseases and cancer. [3][4][5] Chronic lymphocytic leukemia (CLL) is a heterogeneous lymphoproliferative malignancy of clonally expanded CD5 þ CD19 þ B cells. 6 CLL cells are presumably derived from an activated antigen-experienced precursor (IgD þ CD27 þ ).…”

“…Supported by beneficial outcomes following K þ channel blockade in animal models of human diseases 3,4 and clinical trials, 15 we advocate KCa3.1 channels as promising new therapeutic targets in CLL. N ¼ 4).…”

“…4,5 MDS/MPN-U is a rare diagnosis, making up o5% of all myeloid disorders. 6 Accordingly, clinical characteristics and the natural history of patients with MDS/MPN-U are not well established, although poor prognosis among patients with MDS/MPN-U (without RARS-T) has been suggested in small series to date.…”

Activation of human ether-a-go-go related gene (hERG) potassium channels by small molecules

“…hERG channel activators can enhance channel function by accelerating myocardial repolarization, an effect that has been demonstrated by animal experiments, and they are considered potential therapeutics for LQTS. Indeed, hERG activators may become a novel class of antiarrhythmics, as reports have suggested that such compounds can reduce electrical heterogeneity in the myocardium and thereby the possibility of re-entry [20,21] . However, due to the limitations of existing high throughput screening methods and difficulties in assaying the channel on a large scale, few activators have been reported.…”

“…Activation of hERG could provide an alternative and more specific treatment for acquired or congenital LQTS. In addition, hERG activators may become a novel class of antiarrhythmics because, as mentioned above, they can reduce electrical heterogeneity in the myocardium and, thereby, the possibility of re-entry [20,21] . However, this idea has yet to be confirmed clinically.…”