2O2N

Solution structure of the anti-apoptotic protein Bcl-xL in complex with an acyl-sulfonamide-based ligand

2O2N の概要

• エントリーDOI: 10.2210/pdb2o2n/pdb
• 関連するPDBエントリー: 2O1Y 2O21 2O22 2O2F 2O2M
• 分子名称: Apoptosis regulator Bcl-X, 4-[4-(BIPHENYL-2-YLMETHYL)PIPERAZIN-1-YL]-N-[(4-{[1,1-DIMETHYL-2-(PHENYLTHIO)ETHYL]AMINO}-3-NITROPHENYL)SULFONYL]BENZAMIDE (2 entities in total)
• 機能のキーワード: apoptosis, complex, bcl
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Mitochondrion membrane; Single-pass membrane protein (By similarity): Q07817
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 16821.80

構造登録者

Bruncko, M.,Oost, T.K.,Belli, B.A.,Ding, H.,Joseph, M.K.,Kunzer, A.,Martineau, D.,McClellan, W.J.,Mitten, M.,Ng, S.C.,Nimmer, P.M.,Oltersdorf, T.,Park, C.M.,Petros, A.M.,Shoemaker, A.R.,Song, X.,Wang, X.,Wendt, M.D.,Zhang, H.,Fesik, S.W.,Rosenberg, S.H.,Elmore, S.W. (登録日: 2006-11-30, 公開日: 2007-02-27, 最終更新日: 2023-12-27)

主引用文献

Bruncko, M.,Oost, T.K.,Belli, B.A.,Ding, H.,Joseph, M.K.,Kunzer, A.,Martineau, D.,McClellan, W.J.,Mitten, M.,Ng, S.C.,Nimmer, P.M.,Oltersdorf, T.,Park, C.M.,Petros, A.M.,Shoemaker, A.R.,Song, X.,Wang, X.,Wendt, M.D.,Zhang, H.,Fesik, S.W.,Rosenberg, S.H.,Elmore, S.W.
Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL.
J.Med.Chem., 50:641-662, 2007

PubMed Abstract: Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition of these prosurvival proteins is an attractive strategy for cancer therapy. We recently described the discovery of a selective Bcl-xL antagonist that potentiates the antitumor activity of chemotherapy and radiation. Here we describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surface of these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminated in the identification of 2, which exhibited EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2 demonstrated single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given both as a single agent and in combination with etoposide.

PubMed: 17256834
DOI: 10.1021/jm061152t

実験手法

SOLUTION NMR