6P05

Bromodomain-containing protein 4 (BRD4) bromodomain 1 (BD1) complexed with compound 27

6P05 の概要

• エントリーDOI: 10.2210/pdb6p05/pdb
• 分子名称: 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)
• 機能のキーワード: inhibitor, brd4, bromodomain, transcription
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 15860.21

構造登録者

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. (登録日: 2019-05-16, 公開日: 2020-05-20, 最終更新日: 2023-10-11)

主引用文献

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

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: 32453591
DOI: 10.1021/acs.jmedchem.0c00456

実験手法

X-RAY DIFFRACTION (1.54 Å)