4ZBF

Mcl-1 complexed with small molecules

4ZBF の概要

• エントリーDOI: 10.2210/pdb4zbf/pdb
• 関連するPDBエントリー: 4ZBI
• 分子名称: Induced myeloid leukemia cell differentiation protein Mcl-1, (1R)-7-[3-(naphthalen-1-yloxy)propyl]-3,4-dihydro-2H-[1,4]thiazepino[2,3,4-hi]indole-6-carboxylic acid 1-oxide (3 entities in total)
• 機能のキーワード: inhibitor, complex, apoptosis-apoptosis inhibitor complex, apoptosis/apoptosis inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 219405.60

構造登録者

Zhao, B. (登録日: 2015-04-14, 公開日: 2015-04-29, 最終更新日: 2024-03-06)

主引用文献

Burke, J.P.,Bian, Z.,Shaw, S.,Zhao, B.,Goodwin, C.M.,Belmar, J.,Browning, C.F.,Vigil, D.,Friberg, A.,Camper, D.V.,Rossanese, O.W.,Lee, T.,Olejniczak, E.T.,Fesik, S.W.
Discovery of tricyclic indoles that potently inhibit mcl-1 using fragment-based methods and structure-based design.
J.Med.Chem., 58:3794-3805, 2015

PubMed Abstract: Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that is overexpressed and amplified in many cancers. Overexpression of Mcl-1 allows cancer cells to evade apoptosis and contributes to the resistance of cancer cells to be effectively treated with various chemotherapies. From an NMR-based screen of a large fragment library, several distinct chemical scaffolds that bind to Mcl-1 were discovered. Here, we describe the discovery of potent tricyclic 2-indole carboxylic acid inhibitors that exhibit single digit nanomolar binding affinity to Mcl-1 and greater than 1700-fold selectivity over Bcl-xL and greater than 100-fold selectivity over Bcl-2. X-ray structures of these compounds when complexed to Mcl-1 provide detailed information on how these small-molecules bind to the target, which was used to guide compound optimization.

PubMed: 25844895
DOI: 10.1021/jm501984f

実験手法

X-RAY DIFFRACTION (2.2 Å)