Voltage-gated potassium channels as therapeutic targets

Abstract

The human genome encodes 40 voltage-gated K(+) channels (K(V)), which are involved in diverse physiological processes ranging from repolarization of neuronal and cardiac action potentials, to regulating Ca(2+) signalling and cell volume, to driving cellular proliferation and migration. K(V) channels offer tremendous opportunities for the development of new drugs to treat cancer, autoimmune diseases and metabolic, neurological and cardiovascular disorders. This Review discusses pharmacological strategies for targeting K(V) channels with venom peptides, antibodies and small molecules, and highlights recent progress in the preclinical and clinical development of drugs targeting the K(V)1 subfamily, the K(V)7 subfamily (also known as KCNQ), K(V)10.1 (also known as EAG1 and KCNH1) and K(V)11.1 (also known as HERG and KCNH2) channels.

Box 1. Venom peptides and small molecules can interact with Kv channels in multiple ways

Structure of Kv1.2 with the S5-P-S6 region colored green, the voltage-sensor domain colored light grey, the tetramerization domain colored green and the intracellular Kvβ2 subunit magenta. Only two of the four subunits are shown for clarity. Peptide toxins (see for a systematic nomenclature) typically contain between 18 and 60 amino acid residues and are cross-linked by two to four disulfide bridges forming compact molecules, which are remarkably resistant to denaturation. They can affect K_V channels by two different mechanisms. While toxins from scorpions, sea anemones, snakes and cone snails bind to the outer vestibule of K⁺ channels and in most cases insert a lysine side chain into the channel pore to occlude it like a cork a bottle–, spider toxins like hanatoxin, interact with the voltage sensor domain of K_V channels and increase the stability of the closed state,. The resulting rightward shift in activation voltage and acceleration of deactivation means that the channel is more difficult to open (i.e. membrane requires more depolarization) and closes faster. These so-called “gating-modifier” toxins typically contain a cluster of hydrophobic residues on one face of the molecule and seem to partition into the membrane when they bind to the voltage sensor,. In contrast to peptide toxins, which affect K_Vchannels from the extracellular side, most small molecules bind either to the inner pore, the gating-hinges or the interface between the α-and β-subunit.

Figure 1. Theoretical effects of K_V channel inhibitors and activators on pathologically altered neuronal activity

Transmission of information within the nervous system is encoded in the frequency of electrical action potential firing in nerve fibers. Pathological changes in action potential firing frequency within the nervous system can lead to a variety of neurological and psychological disorders. Since K_V channels play important roles in defining the action potential waveform, modulators of these channels are expected to have therapeutic utility in these disorders. For example, under conditions where action potential firing is decreased (i.e. depression, cognitive dysfunction) K_V channel blockers should be able to restore normal firing. K_V channel activators in contrast should be useful to reduce pathological hyperexcitability (i.e. epilepsy, pain) by reducing action potential firing.

Figure 2. Structures of unselective Kv channel blockers and Kv1-family channel modulators. Unselective K_V channel inhibitors:

(1), TBA (tetrabutyl ammonium); (2), d-tubocurarine; (3), verapamil; (4), 4-AP (4-aminopyridine). 4-AP recently completed Phase-3 clinical trials for multiple sclerosis,. Kv1.1 disinactivators: (5), methyl 2,5-dihydroxycinnamate; (6), cylohexadione compound-5 (Wyeth); (7) 1,3-dione-2-carboxamide compound-2 (Wyeth), (8) N-tosyl-2-(3-tosylureido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide compound-6 (Lectus Therapeutics). Kv1.1 disinactivators prevent seizures in miceand have been suggested for the treatment of epilepsy and pain K_V1.3 inhibitors: (9), CP-339818 (Pfizer); (10), UK-78282 (Pfizer); (11), correolide (Merck); (12), PAP-1 (UC Davis); (13), khellinone chalcone (University of Melbourne); (14), 4-substituted khellinone (University of Melbourne); (15), clofazimine. Kv1.3 blockers effectively treat autoimmune disease models in rats and pigs and are therefore regarded as promising new immunosuppressants.

Figure 3. K_V1.5 inhibitors as atrial selective antiarrhythmic agents

a, Schematic of a human atrial and ventricular action potential and the underlying ionic conductances (voltage-gated potassium (K_V) channels shown in green; other classes of ion channel shown in grey) that define the waveform. Kv1.5 (IK_ur) is only expressed in atrial myocytes and K_V1.5 blockers therefore selectively prolong the action potential duration in the atrium. b, Structures of K_V1.5 inhibitors: (16), arylsulphonamidoindane (Icagen/Lilly); (17), AVE0118 (Sanofi-Aventis),; (18), vernakalant (Cardiome),; (19), ISQ-1 (Merck); (20), TAEA (Merck); (21), tetrazole derivative (Procter & Gamble); (22), DPO-1 (Merck). Several Kv1.5 blockers have been or are in clinical trials for the treatment of atrial fibrillation.

Figure 4. K_V7.1 and K_V11.1 are crucial for determining the length of the cardiac action potential

a, Illustration of ventricular action potential (AP) and electrocardiogram (ECG) showing effects of Long- and Short-QT syndrome as well as pharmacological modulators of K_V7.1 (IKs) or K_V11.1 (hERG) on AP duration and length of QT interval. Inhibition of K_V7.1 and K_V11.1 produces prolongation of ventricular AP duration which is similar to what occurs in acquired or hereditary Long QT syndrome. Activators of K_V7.1 or K_V11.1 reduce the duration of cardiac action potential which is manifested as a shorter QT interval b, K_V7.1 inhibitors: (23), azimilide (Procter & Gamble),; (24), HMR1556 (Sanofi-Aventis); (25), L768,673 (Merck). Azimilide has been shown to reduce atrial fibrillation (AF) in clinical trials,, while HMR1556 and L768,673 are effective in dog models of AF. K_V7.1 activators: (26), niflumic acid; (27), mefenamic acid; (28), L384,373 (Merck).

Figure 5. Structures of K_V7.2–7.5 channel modulators

K_V7.2–7.5 inhibitors:(29), linopridine; (30), XE-991; (31), DMP-543. Kv7 channel activators had been proposed to improve learning an memory but failed in clinical trials. Kv7.2–7.5 activators: (32), retigabine (Valeant/GSK)–; (33), flupiritine,; (34), ICA-27243 (Icagen),; (35), Maxiprost/BMS-204352,; (36), acrylaminde compound-24 (BMS),; (37), diclofenac; (38), NH6 (Tel-Aviv University); (39), 2-cyclopentyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide (Lundbeck),. K_V7.2/7.3 activators are effective anticonvulsants in rodent models and clinical trials and have been proposed for the treatment of neuropathic pain, anxiety disorders, mania, migraine, ADHD and schizophrenia based on rodent data.

Figure 6. Modulators of K_V10.1 and K_V11.1

Kv10.1 and Kv11.1 inhibitors:(40), astemizole–; (41), imipramine; (42) dofetilide. Kv10.1 inhibitors have been proposed for the treatment of cancer,. K_V11.1 (hERG) inhibitors prolong the QT interval and can be both antiarrythmic and proarrythmic (e.g. recall of the antihistamine astemizole). K_V11.1 activators: (43) NS1643 (Neurosearch); (44) NS3623 (Neurosearch); (45), RPR260243 (Sanofi-Aventis); (46), PD307243 (GlaxoSmithKline); (47), A935143 (Abbott Laboratories). K_V11.1 activators have been proposed as potential antiarrythmics.