Results of the ERA4Health CARDINNOV Call 2023


SK4 K+ channel blockers: targeting calmodulin-PIP2 interface as new mechanism-based treatment of atrial fibrillation and heart failure


Atrial fibrillation (AF), the most common cardiac arrhythmia, is affecting 1-2% of the population worldwide. Synergistically with heart failure (HF), AF leads to poor clinical outcome and increased mortality. AF has a progressive nature and current therapies, especially in HF patients, are limited in number and efficacy and do not target the underlying atrial inflammation and fibrosis, leaving a substantial unmet need for therapeutic innovation.

The SK4BLOCK-AFHF consortium recently revealed a new druggable  target for AF therapy: the SK4 calcium-activated K+ channel. The SK4 channel is expressed in atrial cardiomyocytes, fibroblasts and macrophages and is upregulated in atria of experimental HF models and clinical AF. The consortium succeeded in designing a novel allosteric blocker, called BA6b9 that targets the calmodulin-PIP2 interface of human SK4 channels. BA6b9 reduces acute AF induction and progression in HF rats.

In the current project, a multidisciplinary consortium will work with complementary expertise and synergy to explore the mechanisms of SK4 K+ channels in AF progression and design optimized BA6b9-derived molecules to test in AF-HF models. Hence, this project will provide insights in SK4 channels as a novel druggable target to effectively prevent the burden of AF in HF patients.


Consortium partners:

Bernard Attali, Tel Aviv, Isreal

Yoram Etzion, Beer-Sheva, Israel

Bianca Brundel, Amsterdam UMC, VUmc

Matteo E. Mangoni, Montpellier, France

David Filgueiras Rama, Madrid, Spain