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SK4 K+ channel blockers: a new treatment for cardiac atrial fibrillation

We discovered a previously unidentified target in the heart, namely the SK4 calcium-activated K+ channels, which are functionally expressed in pacemaker cells as well as in atrial and ventricular cardiomyocytes. They are crucial for proper cardiac function and represent a completely new therapeutic target for the treatment of cardiac arrhythmias. SK4 channel blockers successfully prevented cardiac arrhythmias in in vitro and in vivo models.

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is associated with significant mortality, due to embolic stroke and prevalence within ageing population. In the last decade, pulmonary vein ablation therapy was shown to have favorable anti-AF effects only in selected cases. Nevertheless, this approach is invasive, requires anticoagulants and is limited by cost, complexity, potential life threatening complications and incomplete efficacy because of recurrent AF attacks. Consequently, safe and effective pharmacological treatment options will remain the mainstay therapy for the estimated 30 million North Americans and Europeans that are expected to suffer from AF by 2050.

SK4 K+ channels are important for the late repolarization of the action potential in the atrium and the pacemaker tissue (SAN, AV nodes). As such SK4 channel block will provide an increase in the atrial refractory period with a slowing of AV conduction.

All currently existing SK4 channel blockers interact with the channel pore and display poor bioavailability and liver toxicity. Thus, none of these compounds are currently suitable for further clinical development. We developed a novel allosteric blocker acting to a previously untargeted region of SK4 channels remote from the pore. This allosteric blocker inhibits SK4 channels by interacting with specific residues, thereby preventing the Ca2+-calmodulin to properly open the channel. The drug significantly prolonged atrial and atrioventricular effective refractory periods in rat isolated hearts and reduced AF induction ex vivo. Our novel allosteric blocker inhibits in vivo the AF substrate and atrial fibrosis in rats with post-myocardial infarction. 

Current available therapy for AF like catheter ablation raises questionable effectiveness, especially for patients with diabetes, obesity, hypertension, heart failure and for patients who cannot receive anticoagulant therapy. Several companies try to develop drugs against cardiac arrhythmias by targeting known ion channel targets (Nav, Kv, RyR, GAP junctions) but the pipeline body of new drugs is very thin and does not fill the gap of unmet need. Currently, our project is the sole to propose this new cardiac target: SK4 potassium channel blockers as a new therapy for Atrial Fibrillation. Thanks to their restricted expression, SK4 channels represent an ideal target for therapy.

A US provisional patent application titled “Modulators Of Sk4 Potassium Channel and Uses Thereof” was filed by Ramot on January 17th, 2022 (Ramot reference 2021068)). It is expected to have a long life span due to the long patent protections years ahead and the possibility of layering additional patent applications covering new data that will be generated.

1- Weisbrod D, Peretz A, Ziskind A, Menaker N, Oz S, Barad L, Eliyahu S, Itskovitz-Eldor J, Dascal N, Khananshvili D, Binah O, Attali B. (2013) SK4 Ca2+ activated K+ channel is a critical player in cardiac pacemaker derived from human embryonic stem cells. Proc Natl Acad Sci U S A. 110(18):E1685-94.
2- Weisbrod D, Khun SH, Bueno H, Peretz A, Attali B. (2016) Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels. Acta Pharmacol Sin. 2016 Jan;37(1):82-97.
3- Haron-Khun S, Weisbrod D, Bueno H, Yadin D, Behar J, Peretz A, Binah O, Hochhauser E, Eldar M, Yaniv Y, Arad M and  Attali B. (2017) SK4 K+ channels are therapeutic targets for the treatment of cardiac arrhythmias. EMBO Mol Med. (4):415-429.
4- Shira Burg, Shir Shapiro, Asher Peretz, Elvira Haimov, Boris Redko, Adva Yeheskel, Luba Simhaev, Hamutal Engel, Avi Raveh, Ariel Ben-Bassat, Michael Murninkas, Rotem Polak, Yoni Haitin, Yoram Etzion and Bernard Attali1 (2022) Allosteric inhibitors targeting the calmodulin-PIP2 interface of SK4 K+ channels for atrial fibrillation treatment. Manuscript to be published soon.