Small Molecule Agonists of VDAC2 to Treat Cardiac Arrhythmias and Heart Failure

Summary

Background

Aberrant Ca²⁺ handling in cardiomyocytes is associated with a wide range of human cardiac diseases, including heart failure and arrhythmias. To uncover novel targets implicated in aberrant Ca²⁺ handling, UCLA researchers developed a zebrafish model called tremblor that manifests Ca2+ extrusion defects and fibrillation-like chaotic cardiac contractions as a result ofthe loss of NCX1 sodium/calcium exchanger in cardiomyocytes.

This model was used as a phenotypic screen with a small molecule library developed at UCLA. Small molecules that restore rhythmic and coordinated cardiac contractions in tremblor in vivo were identified in this screen and used to pull down a novel mitochondrial target called VDAC2. This voltage-dependent channel protein plays a key role in maintaining Ca²⁺ homeostasis and may therefore be a novel drug target for atrial and ventricular fibrillation and heart failure.

Mechanistically, these compounds potentiate the Ca²⁺ transporting activity of VDAC2 thereby increasing the rate at which excess Ca²⁺ ions are transferred from the cytoplasm into the mitochondria, restoring normal rhythmic Ca²⁺ transients and suppressing cardiac fibrillation. The best compounds from this screen completely rescue the tremblor fibrillation phenotype in zebrafish and they have also been shown to be active in isolated adult mouse ventricular cardiomyocytes, human and mouse ES cell-derived cardiomyocytes and an initial in vivo rodent study.

The UCLA team is now working to optimize the PK/PD properties of these small molecule VDAC2 agonists and is planning to begin porcine studies in a well-characterized model of ventricular fibrillation.

Applications

Because VDAC2 is a novel drug target for atrial and ventricular fibrillation and heart failure the small molecule agonists under development at UCLA may be drug leads for all of these indications.

Advantages

State Of Development

Patent Status

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• Xie Y, Ottolia M, John SA, Chen JN, Philipson KD. Conformational changes of a Ca2+-binding domain of the Na+/Ca2+ exchanger monitored by FRET in transgenic zebrafish heart. Am J Physiol Cell Physiol. 2008 Aug; 295(2):C388-93.
• Zhang Y, Shimizu H, Siu KL, Mahajan A, Chen JN and Cai H. (2014) NADPH oxidase 4 induces cardiac arrhythmic phenotype in zebrafish. J Biol Chem. 2014 Jun 24.
• Langenbacher AD1, Dong Y, Shu X, Choi J, Nicoll DA, Goldhaber JI, Philipson KD, Chen JN. Mutation in sodium-calcium exchanger 1 (NCX1) causes cardiac fibrillation in zebrafish. Proc Natl Acad Sci U S A. 2005