5IF4

Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) inhibitors using Structure-Based Design

5IF4 の概要

• エントリーDOI: 10.2210/pdb5if4/pdb
• 分子名称: Induced myeloid leukemia cell differentiation protein Mcl-1, 4-{8-chloro-11-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl}-1-methyl-1H-indole-6-carboxylic acid (3 entities in total)
• 機能のキーワード: myeloid cell leukemia-1, bcl-2, apoptosis, 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: 2
• 化学式量合計: 37498.22

構造登録者

Zhao, B. (登録日: 2016-02-25, 公開日: 2017-01-18, 最終更新日: 2024-03-06)

主引用文献

Lee, T.,Bian, Z.,Zhao, B.,Hogdal, L.J.,Sensintaffar, J.L.,Goodwin, C.M.,Belmar, J.,Shaw, S.,Tarr, J.C.,Veerasamy, N.,Matulis, S.M.,Koss, B.,Fischer, M.A.,Arnold, A.L.,Camper, D.V.,Browning, C.F.,Rossanese, O.W.,Budhraja, A.,Opferman, J.,Boise, L.H.,Savona, M.R.,Letai, A.,Olejniczak, E.T.,Fesik, S.W.
Discovery and biological characterization of potent myeloid cell leukemia-1 inhibitors.
FEBS Lett., 591:240-251, 2017

PubMed Abstract: Myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that when overexpressed is associated with high tumor grade, poor survival, and resistance to chemotherapy. Mcl-1 is amplified in many human cancers, and knockdown of Mcl-1 using RNAi can lead to apoptosis. Thus, Mcl-1 is a promising cancer target. Here, we describe the discovery of picomolar Mcl-1 inhibitors that cause caspase activation, mitochondrial depolarization, and selective growth inhibition. These compounds represent valuable tools to study the role of Mcl-1 in cancer and serve as useful starting points for the discovery of clinically useful Mcl-1 inhibitors.

PubMed: 27878989
DOI: 10.1002/1873-3468.12497

実験手法

X-RAY DIFFRACTION (2.392 Å)