Abstract 433: Disrupting the Interaction Between CaM Kinase II and Histone Deacetylase 4 - an Epigenetic Therapy for Heart Failure?

Abstract

CaM Kinase II (CaMKII) critically drives adverse cardiac remodeling. During the process of remodeling, CaMKII binds and phosphorylates Histone Deacetylase 4 (HDAC4), resulting in activation of the transcription factor MEF2. However, it remained unclear whether binding between CaMKII and HDAC4 causes heart failure and whether this interaction represents a novel therapeutic target. We used mouse genetics, HDAC4-based peptides and chemical biology to address these questions. First, we generated CaMKII-resistant HDAC4 mutant mice (CrH) by replacing Arg-598 (corresponds to Arg-601 in humans) of HDAC4 with Phe, because we found Arg-598 to be essential for the CaMKII-HDAC4 interaction. CrH were protected from cardiac dysfunction, hypertrophy and fibrosis in response to both pathological pressure overload or ischemia/reperfusion injury. CrH showed reduced CaMKII binding and less MEF2 activation. These data provided a proof-of-principle that the disruption of the CaMKII-HDAC4 interaction may have therapeutic potential. Thus, in a second step we engineered an HDAC4-derived peptide with homology to the CaMKII binding domain of HDAC4. This peptide competed with HDAC4 for binding with CaMKII, resulting in decreased MEF2 activation and attenuated agonist-induced cardiomyocyte hypertrophy. These data encouraged us to carry the translational pipeline one step further and we screened for small molecules that disrupt the CaMKII-HDAC4 interaction in an in vitro ALPHAScreen Assay (medium-throughput format using 78000 compounds). After a stringent validation process, 38 compounds showed > 40% inhibition. Out of these, 13 compounds effectively inhibited MEF2 activity in a cell-based assay without obvious signs for cellular toxicity, providing now potential cell permeable drug-like candidates. Chemical optimization and in vivo validation strategies are currently ongoing. In summary, we show that the CaMKII-HDAC4 interaction contributes to the development of heart failure and we identified drug-like molecules that specifically disrupt this protein-protein interaction. These findings lay the ground for a novel epigenetic therapeutic approach to combat heart failure.