Targeting Epigenetic Reader Proteins
In recent years, much effort was put into the development of small molecule inhibitors of the bromodomain and extraterminal (BET) family (BRD2, BRD3, BRD4, BRDT) of bromodomain proteins. BET proteins are readers of the ε-N-acetylation of lysine residues (Kac) on histone tails, a modification that is associated with an open chromatin architecture and transcriptional activation. First clinical trials using the BET inhibitors I-BET762 for the treatment of nuclear protein in testis (NUT) midline carcinomas, OTX015 for the treatment of hematological malignancies and CPI-0610 for the treatment of lymphomas have started recently (reviewed in), underscoring the potential of this class of inhibitors. However, BET inhibition as a point of therapeutic intervention also became of interest in autoimmune conditions because of the strong anti-inflammatory properties of BET inhibitors. A first hint for an association of BET proteins with RA came from a study by Mahdi et al. in which specific interactions between genotype, smoking and autoimmunity to citrullinated α-enolase were analyzed. Three SNPs in the BRD2 locus were found to be associated with a subset of RA patients positive for citrullinated α-enolase peptide 1 and cyclic citrullinated peptides, independently of the HLA-DRB1 shared epitope alleles. In addition, a SNP in the locus of another epigenetic reader protein, namely BRD1 (BRPF2) was shown to be protective in joint damage progression in stage I of a GWAS in ACPA RA patients. Recently, therapeutic dosing of the BET inhibitor JQ1 was proven to be efficacious in two mouse models of autoimmunity, the models for CIA and for experimental autoimmune encephalomyelitis (EAE); BET inhibition suppressed the differentiation and activation of Th17 cells. Furthermore, we have shown that the inhibitor I-BET151 suppressed the expression of a broad range of inflammatory mediators and matrix degrading enzymes in RASF in the presence of cytokines or Toll-like receptor (TLR) ligands (Fig. 2). Furthermore, I-BET151 reduced proliferation rates of RASF and chemotactic properties towards PBMC (Klein et al., unpublished). However, the individual roles of BET proteins in mediating effects of different BET inhibitors in inflammatory and autoimmune conditions has hardly been investigated yet.
Targeting epigenetic reader proteins with I-BET151. (a) Acetylated side chains of histones are recognized by the epigenetic reader proteins BRD2, BRD3 and BRD4, leading to the recruitment of effector proteins and the activation of transcription. (b) I-BET151 is a histone mimic that prevents BRD2, BRD3, and BRD4 from binding to acetylated histone side chains, suppresses the transcription of matrix degrading enzymes, inflammatory cytokines and chemokines after stimulation with TNFα, interleukin-1β or Toll-like receptor (TLR) ligands and reduces proliferation rates and the chemoattractive potential of RASF. BET, bromodomain and extraterminal; RASF, rheumatoid arthritis synovial fibroblasts; TNF, tumor necrosis factor.
Besides targeting bromodomain proteins, readers of other epigenetic marks including selected members of methyl-lysine binding site readers were predicted to have good drugability and first inhibitors are in development.