Resverlogix Corp.

BET Inhibition

Epigenetic control over transcriptional programs facilitates appropriate and specific cellular function within each tissue and organ system, in spite of a common genomic sequence shared by every non-germline cell in the body. Adding (writing) and removing (erasing) post-translational modifications – for example, acetylation, methylation and ubiquitination – to the protein components of chromatin is followed by ‘reading’, which dictates gene expression and eventual phenotypic response. Through this mechanism, cellular programs are tightly regulated, yet responsive to stimuli.

Readers – such as those within the bromodomain class of proteins – recognize and bind acetylated lysine residues on histone tails, found in actively transcribing regions of chromatin, and serve as a docking platform for the assembly of large transcriptional complexes and the recruitment of key transcriptional proteins. This family of bromodomain-containing proteins, consisting of approximately 46 diverse nuclear and cytoplasmic proteins, has been the focus of significant drug development efforts in the oncology, autoimmune and vascular disease arena. Bromo and extraterminal (BET) proteins make up a sub-group of the 46 bromodomain-containing proteins and consist of four members: BRD2, BRD3, BRD4 and BRDT. All four BET proteins contain two conserved N-terminal bromodomains (BD1 and BD2), which recognize and bind acetylated lysine residues on histone tails and other nuclear proteins. These interactions localize BET proteins to discrete locations along the chromosome, where they recruit and facilitate assembly of factors to influence gene expression. BET proteins regulate genes that play a part in proliferation, cell cycle progression and apoptosis.

The most advanced BET inhibitor in clinical development is apabetalone (RVX-208). This compound was originally discovered in a screen for Apolipoprotein (Apo) A-I mRNA inducers in hepatocyte cell cultures, and has been shown to raise ApoA-I and high-density lipoprotein (HDL) in humans. Apabetalone binds preferentially to the second bromodomain of BET family members, with a 20-fold or higher selectivity for the second bromodomains of BRD2, BRD3 and BRD4 versus the first bromodomain. This inhibition modulates the expression of a variety of genes including ApoA-I, the core protein component of HDL. Beneficial effects were also observed on CVD biomarkers, such as high-sensitivity C-reactive protein, a marker for systemic inflammation, alkaline phosphatase, a reported key driver for vascular calcification, and components of the complement and coagulation cascades, as well as other mediators of vascular inflammation.

Apabetalone is an inhibitor of BET proteins that modulates and improves multiple biological pathways that drive risk in vascular disease. For more information, please click here for the article "New Direction" in the Summer 2015 Issue of the EBR Journal.