Another emerging approach to drugging the undruggable is to target the bromo and extra C-terminal domain (BET) family of bromodomains that are involved in binding epigenetic “marks” on histone proteins. Four members of this 47-protein family interact with chromatin including histone acetylases and nucleosome remodeling complexes. Bromodomain proteins act as chromatin “readers” to recruit chromatin-regulating enzymes, including “writers” and “erasers” of histone modification, to target promoters and to regulate gene expression. As mentioned in a previous GEN article, epigenetic control systems generally involve three types of proteins: “writers”, “readers”, and “erasers.” Writers attach chemical marks, such as methyl groups (to DNA) or acetyl groups (to the histone proteins that DNA wraps around). Readers bind to these marks, thereby influencing gene expression. Erasers remove the marks.
While investigators have considered that the precise function of the so-called BET bromodomain remains incompletely defined, proteins containing this domain have become another epigenetic target for drug development companies. Importantly, these domains may allow researchers a way to get at oncogenic targets that were once thought undruggable including the proto-oncogene Myc.
Small molecule inhibition of BET protein bromodomains also selectively suppresses other genes such as Bcl-2 that have important roles in cancer, as well as some NF-κB-dependent genes that have roles in both cancer and inflammation. Small molecule inhibition of BET bromodomains leads to selective killing of tumor cells across a range of hematologic malignancies and in subsets of solid tumors. In particular, the bromodomain protein, BRD4, has been identified recently as a therapeutic target in acute myeloid leukemia, multiple myeloma, Burkitt’s lymphoma, human nuclear protein in testis (NUT) midline carcinoma, colon cancer, and inflammatory disease; its loss is a prognostic signature for metastatic breast cancer.
BRD4 also contributes to regulation of both cell cycle and transcription of oncogenes, HIV, and human papilloma virus (HPV). Despite its role in a broad range of biological processes, the precise molecular mechanism of BRD4 function, until very recently, remained unknown.
In 2010, investigators reported in Nature that they had identified a cell-permeable small molecule that bound competitively to bromodomains, or acetyl-lysine recognition motifs. Competitive binding by the small molecule JQ1, the investigators reported, displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models.
The authors say that these data established proof-of-concept for targeting protein–protein interactions of epigenetic readers, and could provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.
More recently, writing in the Journal of Medicinal Chemistry, investigators at GlaxoSmithKline reported that they had successfully optimized a class of benzodiazepines as BET bromodomain inhibitors, apparently without any prior knowledge of identified molecular targets. Significant medicinal chemistry provided the bromodomain inhibitor, I-BET762 or GSK525762, which is currently in a Phase I clinical trial for the treatment of NUT midline carcinoma, a rare but lethal form of cancer, and other cancers.