SAR by Interligand Nuclear Overhauser Effects (ILOEs) Based Discovery of Acylsulfonamide Compounds Active against Bcl-xL and Mcl-1

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• 作者：Michele F. Rega ; Bainan Wu ; Jun Wei ; Ziming Zhang ; Jason F. Cellitti ; Maurizio Pellecchia
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：September 8, 2011
• 年：2011
• 卷：54
• 期：17
• 页码：6000-6013
• 全文大小：1324K
• 年卷期：v.54,no.17(September 8, 2011)
• ISSN：1520-4804

文摘

Overexpression of antiapoptotic members of the Bcl-2 family proteins, such as Bcl-x_L 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-x_L, and Bcl-w while it is not active against Mcl-1 and Bfl-1. However, early clinical and preclinical studies suggest that pan-Bcl-2 antagonists, targeting simultaneously Mcl-1, Bcl-xL, and possibly all other four antiapoptotic 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 Bcl-x_L 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.