TY - JOUR TI - 4-Acyl Pyrroles as Dual BET-BRD7/9 Bromodomain Inhibitors Address BETi Insensitive Human Cancer Cell Lines AU - Hügle, Martin AU - Regenass, Pierre AU - Warstat, Robin AU - Hau, Mirjam AU - Schmidtkunz, Karin AU - Lucas, Xavier AU - Wohlwend, Daniel AU - Einsle, Oliver AU - Jung, Manfred AU - Breit, Bernhard AU - Günther, Stefan T2 - Journal of Medicinal Chemistry AB - 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. DA - 2020/12/04/ PY - 2020 DO - 10.1021/acs.jmedchem.0c00478 DP - ACS Publications J2 - J. Med. Chem. SN - 0022-2623 UR - https://doi.org/10.1021/acs.jmedchem.0c00478 Y2 - 2020/12/09/23:48:47 ER -