5FDR

Mcl-1 complexed with small molecule inhibitor

5FDR の概要

• エントリーDOI: 10.2210/pdb5fdr/pdb
• 関連するPDBエントリー: 4HW2
• 分子名称: Induced myeloid leukemia cell differentiation protein Mcl-1, 5-[[6-chloranyl-3-[3-(4-chloranyl-3,5-dimethyl-phenoxy)propyl]-7-(3,5-dimethyl-1~{H}-pyrazol-4-yl)-1~{H}-indol-2-yl]carbonylsulfamoyl]furan-2-carboxylic acid (2 entities in total)
• 機能のキーワード: mcl-1, inhibitor, 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: 4
• 化学式量合計: 74499.62

構造登録者

Zhao, B. (登録日: 2015-12-16, 公開日: 2016-03-02, 最終更新日: 2023-09-27)

主引用文献

Pelz, N.F.,Bian, Z.,Zhao, B.,Shaw, S.,Tarr, J.C.,Belmar, J.,Gregg, C.,Camper, D.V.,Goodwin, C.M.,Arnold, A.L.,Sensintaffar, J.L.,Friberg, A.,Rossanese, O.W.,Lee, T.,Olejniczak, E.T.,Fesik, S.W.
Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods.
J.Med.Chem., 59:2054-2066, 2016

PubMed Abstract: Myeloid cell leukemia-1 (Mcl-1) is a member of the Bcl-2 family of proteins responsible for the regulation of programmed cell death. Amplification of Mcl-1 is a common genetic aberration in human cancer whose overexpression contributes to the evasion of apoptosis and is one of the major resistance mechanisms for many chemotherapies. Mcl-1 mediates its effects primarily through interactions with pro-apoptotic BH3 containing proteins that achieve high affinity for the target by utilizing four hydrophobic pockets in its binding groove. Here we describe the discovery of Mcl-1 inhibitors using fragment-based methods and structure-based design. These novel inhibitors exhibit low nanomolar binding affinities to Mcl-1 and >500-fold selectivity over Bcl-xL. X-ray structures of lead Mcl-1 inhibitors when complexed to Mcl-1 provided detailed information on how these small-molecules bind to the target and were used extensively to guide compound optimization.

PubMed: 26878343
DOI: 10.1021/acs.jmedchem.5b01660

実験手法

X-RAY DIFFRACTION (2.6 Å)