SAR by interligand nuclear overhauser effects (ILOEs) based discovery of acylsulfonamide compounds active against Bcl-x(L) and Mcl-1.
SAR by interligand nuclear overhauser effects (ILOEs) based discovery of acylsulfonamide compounds active against Bcl-x(L) and Mcl-1.
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DOI：
10.1021/jm200826s
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发表时间：
2011-09-08
影响因子：
7.3
通讯作者：
Pellecchia, Maurizio
中科院分区：
文献类型：
--
作者：
Rega, Michele F.;Wu, Bainan;Wei, Jun;Zhang, Ziming;Cellitti, Jason F.;Pellecchia, Maurizio
Bcl-2家族抗凋亡成员，如Bcl-xL和Mfl-1的过度表达已被证明与多种癌症对化疗药物的耐药性有关。最近，雅培实验室开发了一种酰基磺胺化合物和临床候选物，可选择性靶向Bcl-2、Bcl-xL和Bcl-w，而对Mcl-1和bcl -1无活性。然而，早期临床和临床前研究表明，同时靶向Mcl-1、Bcl-xL和可能所有其他四种抗凋亡Bcl-2蛋白的泛Bcl-2拮抗剂可能会产生更有效的药物。在这里，采用基于核磁共振片段的方法，通过ILOEs进行SAR，我们报道了在体外对BclxL和Mcl-1都具有纳米摩尔亲和力的化合物。我们相信这些分子可以作为开发新型Bcl-2拮抗剂的有用起点，特别是针对Mcl-1。
Over expression of anti-apoptotic members of the Bcl-2 family proteins, such as Bcl-xL and Mfl-1 has been shown to be involved in resistance to chemotherapeutic drugs in many forms of cancers. Recent efforts from the Abbott Laboratories resulted in the development of the acylsulfonamide compound and clinical candidate that targets selectively Bcl-2, Bcl-xL and Bcl-w while is not active against Mcl-1 and Bfl-1. However, early clinical and pre-clinical studies suggest that pan-Bcl-2 antagonists, targeting simultaneously Mcl-1, Bcl-xL and possibly all other four anti-apoptotic Bcl-2 proteins, may result in more efficacious drugs. Here, following an NMR fragment-based approach, SAR by ILOEs, we report on compounds that exhibit nanomolar affinities for both BclxL and Mcl-1 in vitro. We believe that these molecules can be used as useful starting point for the development of novel Bcl-2 antagonists, in particular targeting Mcl-1.
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影响因子：
7.3
作者：
Mayer, M;Meyer, B
通讯作者：
Meyer, B
影响因子：
5.1
作者：
Rega, Michele F.;Leone, Marilisa;Pellecchia, Maurizio
通讯作者：
Pellecchia, Maurizio
影响因子：
9
作者：
通讯作者：
--
DOI：
10.1016/0006-291x(80)90695-6
发表时间：
1980-01-01
影响因子：
3.1
作者：
KUMAR, A;ERNST, RR;WUTHRICH, K
通讯作者：
WUTHRICH, K
DOI：
10.1073/pnas.0701297104
发表时间：
2007-04-10
影响因子：
11.1
作者：
Czabotar, Peter E.;Lee, Erinna F.;Colman, Peter M.
通讯作者：
Colman, Peter M.