Watch this video to learn about the mechanism of action of our lead epigenetic regulator, larsucosterol (DUR-928).

The epigenome is made up of chemical compounds and proteins that can attach to the DNA and regulate gene expression without modifying the DNA sequence. Epigenetic regulation is a natural process of development, directing tissue differentiation and organ development. Its alteration may result in disease and disease processes can lead to its dysregulation.

DNA methylation is one of the mechanisms of such epigenetic modulation.

For instance, DNMTs are epigenetic regulating enzymes that add methyl groups to the cytosine nucleotides of DNA, in a process called methylation.

Methylation at the promoter regions will generally decrease gene expression, while demethylation at the promoter regions increases gene expression.  DNA methylation and demethylation can thus regulate the expression of relevant genes, especially clusters of master genes that further modulate crucial cellular activities.

DNA hypermethylation has been associated with certain diseases. 

Larsucosterol, DURECT’s lead program, is an endogenous sulfated oxysterol that acts as an epigenetic regulator. Larsucosterol has been shown to bind and inhibit the activity of DNMTs, including DNMT-1, 3a and 3b.  By inhibiting DNMT activity, larsucosterol inhibits DNA methylation thereby regulating the expression of genes that modulate crucial cellular activities including those associated with cell death, stress response, and lipid biosynthesis.These modulations may lead to improved cell survival, and reduced lipotoxicity and inflammation.

Given its proposed mechanism of action as an epigenetic regulator, there is scientific rationale for investigating larsucosterol for the treatment of acute organ injury and certain chronic diseases, such as alcohol-associated hepatitis and NASH.