BA6b9

BA6b9 (also referred to as BAb69) is a novel, selective, small-molecule allosteric inhibitor of the intermediate conductance calcium-activated potassium channel protein 4 (SK4/KCa3.1). It was designed to target the cytosol-facing calmodulin (CaM)–phosphatidylinositol 4,5-bisphosphate (PIP2) binding domain (CPBD) at the interface of the proximal carboxyl terminus and the S4–S5 linker of the SK4 channel. By interacting with specific residues (Arg191 and His192) in the S4–S5 linker, BA6b9 prevents the calcium-bound calmodulin N-lobe from properly interacting with the channel, thereby inhibiting channel gating. BA6b9 is being developed by a multidisciplinary consortium including Tel Aviv University, Ben-Gurion University of the Negev, and Amsterdam UMC for the treatment of atrial fibrillation (AF) and heart failure (HF). In preclinical models, BA6b9 has been shown to prolong the atrial effective refractory period, reduce AF susceptibility, and prevent adverse atrial structural remodeling, including inflammation and fibrosis.