Discovery of a potent inhibitor of the antiapoptotic protein Bcl-xL from NMR and parallel synthesis

被引：243

作者：

Petros, AM ^{[1
]}

Dinges, J ^{[1
]}

Augeri, DJ ^{[1
]}

Baumeister, SA ^{[1
]}

Betebenner, DA ^{[1
]}

Bures, MG ^{[1
]}

Elmore, SW ^{[1
]}

Hajduk, PJ ^{[1
]}

Joseph, MK ^{[1
]}

Landis, SK ^{[1
]}

Nettesheim, DG ^{[1
]}

Rosenberg, SH ^{[1
]}

Shen, W ^{[1
]}

Thomas, S ^{[1
]}

Wang, XL ^{[1
]}

Zanze, I ^{[1
]}

Zhang, HC ^{[1
]}

Fesik, SW ^{[1
]}

机构：

[1] Abbott Labs, Global Pharmaceut Res & Dev, Abbott Pk, IL 60064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 02期

关键词：

D O I：

10.1021/jm0507532

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The antiapoptotic proteins Bcl-x(L) and Bcl-2 play key roles in the maintenance of normal cellular homeostasis. However, their overexpression can lead to oncogenic transformation and is responsible for drug resistance in certain types of cancer. This makes Bcl-x(L) and Bcl-2 attractive targets for the development of potential anticancer agents. Here we describe the structure-based discovery of a potent Bcl-x(L) inhibitor directed at a hydrophobic groove on the surface of the protein. This groove represents the binding site for BH3 peptides from proapoptotic Bcl-2 family members such as Bak and Bad. Application of NMR-based screening yielded an initial biaryl acid with an affinity (K-d) of similar to 300 mu M for the protein. Following the classical "SAR by NMR" approach, a second-site ligand was identified that bound proximal to the first-site ligand in the hydrophobic groove. From NMR-based structural studies and parallel synthesis, a potent ligand was obtained, which binds to Bcl-x(L) with an inhibition constant (K-i) of 36 +/- 2 nM.

引用

页码：656 / 663

页数：8

共 25 条

[1] The Bcl-2 protein family: Arbiters of cell survival [J].

Adams, JM ;

Cory, S .

SCIENCE, 1998, 281 (5381) :1322-1326

[2] Small-molecule inhibitors of protein-protein interactions: Progressing towards the dream [J].

Arkin, MR ;

Wells, JA .

NATURE REVIEWS DRUG DISCOVERY, 2004, 3 (04) :301-317

[3] CLUSTERING OF CHEMICAL STRUCTURES ON THE BASIS OF 2-DIMENSIONAL SIMILARITY MEASURES [J].

BARNARD, JM ;

DOWNS, GM .

JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES, 1992, 32 (06) :644-649

[4] An evaluation of structural descriptors and clustering methods for use in diversity selection [J].

Brown, RD ;

Martin, YC .

SAR AND QSAR IN ENVIRONMENTAL RESEARCH, 1998, 8 (1-2) :23-39

[5]

BRUNGER AT, 1992, XPLOR VERSION 3 1

[6] The Bcl-2 family: roles in cell survival and oncogenesis [J].

Cory, S ;

Huang, DCS ;

Adams, JM .

ONCOGENE, 2003, 22 (53) :8590-8607

[7]

CRAIG PN, 1980, BASIS MED CHEM

[8] STRATEGY IN DRUG DESIGN - CLUSTER ANALYSIS AS AN AID IN SELECTION OF SUBSTITUENTS [J].

HANSCH, C ;

UNGER, SH ;

FORSYTHE, AB .

JOURNAL OF MEDICINAL CHEMISTRY, 1973, 16 (11) :1217-1222

[9] Shooting at survivors: Bcl-2 family members as drug targets for cancer [J].

Juin, P ;

Geneste, O ;

Raimbaud, E ;

Hickman, JA .

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 2004, 1644 (2-3) :251-260

[10]

Kitrkin V., 2004, BIOCHIM BIOPHYS ACTA, V1644, P229

← 1 2 3 →