5WMD

N-terminal bromodomain of BRD4 in complex with OTX-015

5WMD の概要

• エントリーDOI: 10.2210/pdb5wmd/pdb
• 分子名称: Bromodomain-containing protein 4, 2-[(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]-N-(4-hydroxyphenyl)acetamide (3 entities in total)
• 機能のキーワード: bromodomain, brd4, transcription, otx-015, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• 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: 15517.34

構造登録者

Zhang, Y. (登録日: 2017-07-28, 公開日: 2018-08-01, 最終更新日: 2023-10-04)

主引用文献

Ozer, H.G.,El-Gamal, D.,Powell, B.,Hing, Z.A.,Blachly, J.S.,Harrington, B.,Mitchell, S.,Grieselhuber, N.R.,Williams, K.,Lai, T.H.,Alinari, L.,Baiocchi, R.A.,Brinton, L.,Baskin, E.,Cannon, M.,Beaver, L.,Goettl, V.M.,Lucas, D.M.,Woyach, J.A.,Sampath, D.,Lehman, A.M.,Yu, L.,Zhang, J.,Ma, Y.,Zhang, Y.,Spevak, W.,Shi, S.,Severson, P.,Shellooe, R.,Carias, H.,Tsang, G.,Dong, K.,Ewing, T.,Marimuthu, A.,Tantoy, C.,Walters, J.,Sanftner, L.,Rezaei, H.,Nespi, M.,Matusow, B.,Habets, G.,Ibrahim, P.,Zhang, C.,Mathe, E.A.,Bollag, G.,Byrd, J.C.,Lapalombella, R.
BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor.
Cancer Discov, 8:458-477, 2018

PubMed Abstract: Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is overexpressed in CLL and is enriched proximal to genes upregulated or expressed in CLL with known functions in disease pathogenesis and progression. These genes, including key members of the B-cell receptor (BCR) signaling pathway, provide a rationale for this therapeutic approach to identify new targets in alternative types of cancer. Additionally, we describe PLX51107, a structurally distinct BET inhibitor with novel and pharmacologic properties that emulates or exceeds the efficacy of BCR signaling agents in preclinical models of CLL. Herein, the discovery of the involvement of BRD4 in the core CLL transcriptional program provides a compelling rationale for clinical investigation of PLX51107 as epigenetic therapy in CLL and application of BRD4 profiling in other cancers. To date, functional studies of BRD4 in CLL are lacking. Through integrated genomic, functional, and pharmacologic analyses, we uncover the existence of BRD4-regulated core CLL transcriptional programs and present preclinical proof-of-concept studies validating BET inhibition as an epigenetic approach to target BCR signaling in CLL. .

PubMed: 29386193
DOI: 10.1158/2159-8290.CD-17-0902

実験手法

X-RAY DIFFRACTION (1.27 Å)