6P05
Bromodomain-containing protein 4 (BRD4) bromodomain 1 (BD1) complexed with compound 27
Summary for 6P05
| Entry DOI | 10.2210/pdb6p05/pdb |
| Descriptor | Bromodomain-containing protein 4, GLYCEROL, N-{1-[1,1-di(pyridin-2-yl)ethyl]-6-(1-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-3-yl)-1H-indol-4-yl}ethanesulfonamide, ... (4 entities in total) |
| Functional Keywords | inhibitor, brd4, bromodomain, transcription |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 15860.21 |
| Authors | Ratia, K.M.,Xiong, R.,Li, Y.,Zhao, J.,Gutgesell, L.M.,Shen, Z.,Dye, K.,Dubrovyskyii, O.,Zhao, H.,Huang, F.,Tonetti, D.A.,Thatcher, G.R. (deposition date: 2019-05-16, release date: 2020-05-20, Last modification date: 2023-10-11) |
| Primary citation | Li, Y.,Zhao, J.,Gutgesell, L.M.,Shen, Z.,Ratia, K.,Dye, K.,Dubrovskyi, O.,Zhao, H.,Huang, F.,Tonetti, D.A.,Thatcher, G.R.J.,Xiong, R. Novel Pyrrolopyridone Bromodomain and Extra-Terminal Motif (BET) Inhibitors Effective in Endocrine-Resistant ER+ Breast Cancer with Acquired Resistance to Fulvestrant and Palbociclib. J.Med.Chem., 63:7186-7210, 2020 Cited by PubMed Abstract: Acquired resistance to fulvestrant and palbociclib is a new challenge to treatment of estrogen receptor positive (ER+) breast cancer. ER is expressed in most resistance settings; thus, bromodomain and extra-terminal protein inhibitors (BETi) that target BET-amplified ER-mediated transcription have therapeutic potential. Novel pyrrolopyridone BETi leveraged novel interactions with L92/L94 confirmed by a cocrystal structure of with BRD4. Optimization of BETi using growth inhibition in fulvestrant-resistant (MCF-7:CFR) cells was confirmed in endocrine-resistant, palbociclib-resistant, and mutant cell lines. was more potent in MCF-7:CFR cells than six BET inhibitors in clinical trials. Transcriptomic analysis differentiated from the benchmark BETi, JQ-1, showing downregulation of oncogenes and upregulation of tumor suppressors and apoptosis. The therapeutic approach was validated by oral administration of in orthotopic xenografts of endocrine-resistant breast cancer in monotherapy and in combination with fulvestrant. Importantly, at an equivalent dose in rats, thrombocytopenia was mitigated. PubMed: 32453591DOI: 10.1021/acs.jmedchem.0c00456 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.54 Å) |
Structure validation
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