4‑Acyl Pyrroles as Dual BET-BRD7/9 Bromodomain Inhibitors Address BETi Insensitive Human Cancer Cell Lines

Various
malignant human diseases show disturbed signaling pathways
due to increased activity of proteins within the epigenetic machinery.
Recently, various novel inhibitors for epigenetic regulation have
been introduced which promise a great therapeutic benefit. Inhibitors
for the bromo- and extra-terminal domain (BET) family were of particular
interest after inhibitors had shown a strong antiproliferative effect.
More recently, the focus has increasingly shifted to bromodomains
(BDs) outside the BET family. Based on previously developed inhibitors,
we have optimized a small series of 4-acyl pyrroles, which we further
analyzed by ITC, X-ray crystallography, selectivity studies, the NCI60
cell-panel, and GI50 determinations for several cancer
cell lines. The inhibitors address both, BET and BRD7/9 BDs, with
very high affinity and show a strong antiproliferative effect on various
cancer cell lines that could not be observed for BD family selective
inhibitors. Furthermore, a synergistic effect on breast cancer (MCF-7)
and melanoma (SK-MEL-5) was proven.