5S9O

CRYSTAL STRUCTURE OF THE HUMAN BRD2 BD1 BROMODOMAIN IN COMPLEX WITH 9-(cyclopropylmethyl)-7-[(2R,6S)-2,6-dimethylmorpholine-4-carbonyl]-3-(3,5-dimethyl-1,2-oxazol-4-yl)-9H-carbazole-1-carboxamide

5S9O の概要

• エントリーDOI: 10.2210/pdb5s9o/pdb
• Group deposition: BET (G_1002195)
• 分子名称: Bromodomain-containing protein 2, 9-(cyclopropylmethyl)-7-[(2R,6S)-2,6-dimethylmorpholine-4-carbonyl]-3-(3,5-dimethyl-1,2-oxazol-4-yl)-9H-carbazole-1-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: helical bundle, acetyl-lysine recognition, acetylated histone h4, nucleus, transcription-transcription inhibitor complex, cell cycle
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 35525.00

構造登録者

Sheriff, S. (登録日: 2021-04-01, 公開日: 2021-09-29, 最終更新日: 2024-05-22)

主引用文献

Gavai, A.V.,Norris, D.,Delucca, G.,Tortolani, D.,Tokarski, J.S.,Dodd, D.,O'Malley, D.,Zhao, Y.,Quesnelle, C.,Gill, P.,Vaccaro, W.,Huynh, T.,Ahuja, V.,Han, W.C.,Mussari, C.,Harikrishnan, L.,Kamau, M.,Poss, M.,Sheriff, S.,Yan, C.,Marsilio, F.,Menard, K.,Wen, M.L.,Rampulla, R.,Wu, D.R.,Li, J.,Zhang, H.,Li, P.,Sun, D.,Yip, H.,Traeger, S.C.,Zhang, Y.,Mathur, A.,Zhang, H.,Huang, C.,Yang, Z.,Ranasinghe, A.,Everlof, G.,Raghavan, N.,Tye, C.K.,Wee, S.,Hunt, J.T.,Vite, G.,Westhouse, R.,Lee, F.Y.
Discovery and Preclinical Pharmacology of an Oral Bromodomain and Extra-Terminal (BET) Inhibitor Using Scaffold-Hopping and Structure-Guided Drug Design.
J.Med.Chem., 64:14247-14265, 2021

PubMed Abstract: Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the screening hit , a combination of structure-activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of (BMS-986158) with excellent potency in binding and functional assays. On the basis of its favorable PK profile and robust in vivo activity in a panel of hematologic and solid tumor models, BMS-986158 was selected as a candidate for clinical evaluation.

PubMed: 34543572
DOI: 10.1021/acs.jmedchem.1c00625

実験手法

X-RAY DIFFRACTION (2.49 Å)