9FBX

C-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH 5-(1-benzyl-4-chloro-1H-imidazol-2-yl)-1,3-dimethylpyridin-2(1H)-one

これはPDB形式変換不可エントリーです。

9FBX の概要

• エントリーDOI: 10.2210/pdb9fbx/pdb
• 分子名称: Bromodomain-containing protein 2, 1,2-ETHANEDIOL, 2-{2-[2-(2-{2-[2-(2-ETHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL, ... (5 entities in total)
• 機能のキーワード: bet, bromodomain, inhibitor, epigenetic, 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: 14224.82

構造登録者

Chung, C. (登録日: 2024-05-14, 公開日: 2024-06-26, 最終更新日: 2024-07-10)

主引用文献

Hirst, D.J.,Bamborough, P.,Al-Mahdi, N.,Angell, D.C.,Barnett, H.A.,Baxter, A.,Bit, R.A.,Brown, J.A.,Chung, C.W.,Craggs, P.D.,Davis, R.P.,Demont, E.H.,Ferrie, A.,Gordon, L.J.,Harada, I.,Ho, T.C.T.,Holyer, I.D.,Hooper-Greenhill, E.,Jones, K.L.,Lindon, M.J.,Lovatt, C.,Lugo, D.,Maller, C.,McGonagle, G.,Messenger, C.,Mitchell, D.J.,Pascoe, D.D.,Patel, V.K.,Patten, C.,Poole, D.L.,Shah, R.R.,Rioja, I.,Stafford, K.A.J.,Tape, D.,Taylor, S.,Theodoulou, N.H.,Tomlinson, L.,Wall, I.D.,Wellaway, C.R.,White, G.,Prinjha, R.K.,Humphreys, P.G.
Structure- and Property-Based Optimization of Efficient Pan-Bromodomain and Extra Terminal Inhibitors to Identify Oral and Intravenous Candidate I-BET787.
J.Med.Chem., 67:10464-10489, 2024

PubMed Abstract: The bromodomain and extra terminal (BET) family of bromodomain-containing proteins are important epigenetic regulators that elicit their effect through binding histone tail -acetyl lysine (KAc) post-translational modifications. Recognition of such markers has been implicated in a range of oncology and immune diseases and, as such, small-molecule inhibition of the BET family bromodomain-KAc protein-protein interaction has received significant interest as a therapeutic strategy, with several potential medicines under clinical evaluation. This work describes the structure- and property-based optimization of a ligand and lipophilic efficient pan-BET bromodomain inhibitor series to deliver candidate I-BET787 () that demonstrates efficacy in a mouse model of inflammation and suitable properties for both oral and intravenous (IV) administration. This focused two-phase explore-exploit medicinal chemistry effort delivered the candidate molecule in 3 months with less than 100 final compounds synthesized.

PubMed: 38866424
DOI: 10.1021/acs.jmedchem.4c00959

実験手法

X-RAY DIFFRACTION (1.602 Å)