Dilated cardiomyopathy (DCM) is a form of heart muscle weakness. Firstly, it shows the reduction of cardiac output, as well as thinning and enlargement of left ventricular chambers. Secondly, DCM accounts for 30 to 40% of all heart failure cases in clinical trials and is a major cause of heart transplants. In addition, about one-third of individuals with DCM have an inherited form of the disease.

Mutations in BAG3 correlate with DCM and most mutations in BAG3 are deleterious. In several studies, mutations in BAG3 led to cardiac-related phenotypes both in vivo and in vitro, in zebrafish, mice, and human-induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). Today, we will introduce an HDAC6 inhibitor — TYA-018. It shows protected heart function in a BAG3 cardiomyocyte-knockout (BAG3c^KO) mouse model of DCM.

TYA-018 is an orally active HDAC6 inhibitor and can be used for the research of dilated cardiomyopathy disease

In vitro DCM model use iPSC-CMs deficient in B-cell lymphoma 2 (BCL2)-associated athanogene 3 (BAG3). And from a library of 5500 bioactive compounds and siRNA validation, the research found that inhibiting HDAC6 was cardioprotective at the sarcomere level.

Firstly, a BAG3c^KO mouse model of DCM, showed that inhibiting HDAC6 with isoform-selective inhibitors (TYA-018) protected heart function. Secondly, TYA-018 protected against sarcomere damage and reduced Nppb expression. Meanwhile, in BAG3c^KO and BAG3^E455K mice, TYA-018 improved left ventricular ejection fraction and reduced left ventricular diameter at diastole and systole. Furthermore, Based on integrated transcriptomics and proteomics, and mitochondrial function analysis, TYA-018 also enhanced energetics in these mice by increasing the expression of targets associated with fatty acid metabolism, protein metabolism, and oxidative phosphorylation.

In sum, TYA-018 is an Orally Active HDAC6 Inhibitor for Dilated cardiomyopathy research.

Reference:

[1] Yang J, et al. Sci Transl Med. 2022 Jul 6;14(652):eabl5654.