Bromodomain Drug Discovery – the Past, the Present, and the Future

Abstract

With the bromodomain (BRD) inhibitor JQ1, a remarkable success story of BRD4 as a novel drug target has been set off that yielded many anti‐cancer drugs that are now in clinical trials. But not all of the great prospects of BRDs as drug targets may become true. First evaluations of ongoing clinical trials revealed that treatment with BET‐inhibitors can be accompanied with significant toxic side effects and the validation of the therapeutic benefit of BET‐inhibitors compared to existing therapies is still pending. New strategies that may overcome possible obstacles in BRD drug discovery include combination therapies with other agents, dual target inhibitors, and proteolysis targeting chimeras (PROTACs). Furthermore, non‐BET proteins seem promising drug targets as well. Most recently, BRDs have been identified as putative targets to treat parasitic diseases such as malaria. Milestones in BRD drug discovery are reviewed and promising new developments are evaluated.

The Role of MYC and PP2A in the Initiation and Progression of Myeloid Leukemias

“…Some BET inhibitors are currently in early phase clinical trials for treating hematopoietic malignancies and solid tumors with exciting results [132]. However, toxic side effects [133] and cases of resistance have been reported [134].…”

Cyclic peptides can engage a single binding pocket through multiple, entirely divergent modes

“…Inhibition of the BET family of bromodomains has shown considerable promise for a range of different pathologies [12][13][14][15][16] . Indeed, more than two dozen clinical trials are currently underway against a variety of malignancies including acute myeloid leukemia, lymphoma and ER+ breast cancer [17][18][19] . Despite heavy academic and industry investment in this area, however, the generation of paralogue-selective inhibitors has proved elusive because of the extremely high sequence similarity between the bromodomains of family members (90-95% within the acetyllysine binding pocket residues).…”

“…Despite heavy academic and industry investment in this area, however, the generation of paralogue-selective inhibitors has proved elusive because of the extremely high sequence similarity between the bromodomains of family members (90-95% within the acetyllysine binding pocket residues). This lack of selectivity not only raises issues for the use of BET BD inhibitors as therapeutics, but also limits our ability to probe the mechanisms by which individual BET family members direct gene expression 17 .…”

A combination strategy targeting enhancer plasticity exerts synergistic lethality against BETi-resistant leukemia cells

“…BET inhibitors (BETi), as exemplified by JQ1 and I-BET151, have been shown to suppress the growth of multiple types of tumor both in vitro and in vivo 8 . However, potential drug resistance associated with BETi becomes one of the major hurdles hampering the clinical applications of these promising drug candidates 8,9 .…”