The Role of the Acidity of N-Heteroaryl Sulfonamides as Inhibitors of Bcl-2 Family Protein-Protein Interactions

被引：52

作者：

Toure, B. Barry ^{[1
]}

Miller-Moslin, Karen ^{[1
]}

Yusuff, Naeem ^{[1
]}

Perez, Lawrence ^{[1
]}

Dore, Michael ^{[1
]}

Joud, Carol ^{[1
]}

Michael, Walter ^{[1
]}

DiPietro, Lucian ^{[1
]}

van der Plas, Simon ^{[1
]}

McEwan, Michael ^{[1
]}

Lenoir, Francois ^{[1
]}

Hoe, Madelene ^{[1
]}

Karki, Rajesh ^{[1
]}

Springer, Clayton ^{[1
]}

Sullivan, John ^{[1
]}

Levine, Kymberly ^{[1
]}

Fiorilla, Catherine ^{[1
]}

Xie, Xiaoling ^{[1
]}

Kulathila, Raviraj ^{[1
]}

Herlihy, Kara ^{[1
]}

Porter, Dale ^{[1
]}

Visser, Michael ^{[1
]}

机构：

[1] Novartis Inst BioMed Res Inc, Cambridge, MA 02139 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2013年 / 4卷 / 02期

关键词：

B cell lymphoma; Bcl-2; family; protein-protein interaction; apoptosis; cancer; DISCOVERY; ANTAGONISTS; PRODRUGS;

D O I：

10.1021/ml300321d

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Overexpression of the antiapoptotic members of the Bcl-2 family of proteins is commonly associated with cancer cell survival and resistance to chemotherapeutics. Here, we describe the structure-based optimization of a series of N-heteroaryl sulfonamides that demonstrate potent mechanism-based cell death. The role of the acidic nature of the sulfonamide moiety as it relates to potency, solubility, and clearance is examined. This has led to the discovery of novel heterocyclic replacements for the acylsulfonamide core of ABT-737 and ABT-263.

引用

页码：186 / 190

页数：5

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