5MW2

CRYSTAL STRUCTURE OF BCL-6 BTB-domain with BI-3802

5MW2 の概要

• エントリーDOI: 10.2210/pdb5mw2/pdb
• 分子名称: B-cell lymphoma 6 protein, 2-[6-[[5-chloranyl-2-[(3~{S},5~{R})-3,5-dimethylpiperidin-1-yl]pyrimidin-4-yl]amino]-1-methyl-2-oxidanylidene-quinolin-3-yl]oxy-~{N}-methyl-ethanamide (3 entities in total)
• 機能のキーワード: transcription, inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : P41182
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 14987.75

構造登録者

Bader, G.,Flotzinger, G.,Weiss-Puxbaum, A.,Zoephel, A. (登録日: 2017-01-18, 公開日: 2017-10-04, 最終更新日: 2024-05-08)

主引用文献

Kerres, N.,Steurer, S.,Schlager, S.,Bader, G.,Berger, H.,Caligiuri, M.,Dank, C.,Engen, J.R.,Ettmayer, P.,Fischerauer, B.,Flotzinger, G.,Gerlach, D.,Gerstberger, T.,Gmaschitz, T.,Greb, P.,Han, B.,Heyes, E.,Iacob, R.E.,Kessler, D.,Kolle, H.,Lamarre, L.,Lancia, D.R.,Lucas, S.,Mayer, M.,Mayr, K.,Mischerikow, N.,Muck, K.,Peinsipp, C.,Petermann, O.,Reiser, U.,Rudolph, D.,Rumpel, K.,Salomon, C.,Scharn, D.,Schnitzer, R.,Schrenk, A.,Schweifer, N.,Thompson, D.,Traxler, E.,Varecka, R.,Voss, T.,Weiss-Puxbaum, A.,Winkler, S.,Zheng, X.,Zoephel, A.,Kraut, N.,McConnell, D.,Pearson, M.,Koegl, M.
Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6.
Cell Rep, 20:2860-2875, 2017

PubMed Abstract: The transcription factor BCL6 is a known driver of oncogenesis in lymphoid malignancies, including diffuse large B cell lymphoma (DLBCL). Disruption of its interaction with transcriptional repressors interferes with the oncogenic effects of BCL6. We used a structure-based drug design to develop highly potent compounds that block this interaction. A subset of these inhibitors also causes rapid ubiquitylation and degradation of BCL6 in cells. These compounds display significantly stronger induction of expression of BCL6-repressed genes and anti-proliferative effects than compounds that merely inhibit co-repressor interactions. This work establishes the BTB domain as a highly druggable structure, paving the way for the use of other members of this protein family as drug targets. The magnitude of effects elicited by this class of BCL6-degrading compounds exceeds that of our equipotent non-degrading inhibitors, suggesting opportunities for the development of BCL6-based lymphoma therapeutics.

PubMed: 28930682
DOI: 10.1016/j.celrep.2017.08.081

実験手法

X-RAY DIFFRACTION (2.35 Å)