Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods
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- 作者：Nicholas F. Pelz ; Zhiguo Bian ; Bin Zhao ; Subrata Shaw ; James C. Tarr ; Johannes Belmar ; Claire Gregg ; DeMarco V. Camper ; Craig M. Goodwin ; Allison L. Arnold ; John L. Sensintaffar ; Anders Friberg ; Olivia W. Rossanese ; Taekyu Lee ; Edward T. Olejniczak ; Stephen W. Fesik
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：March 10, 2016
- 年：2016
- 卷：59
- 期：5
- 页码：2054-2066
- 全文大小：869K
- ISSN：1520-4804
文摘
Myeloid cell leukemia-1 (Mcl-1) is a member of the Bcl-2 family of proteins responsible for the regulation of programmed cell death. Amplification of Mcl-1 is a common genetic aberration in human cancer whose overexpression contributes to the evasion of apoptosis and is one of the major resistance mechanisms for many chemotherapies. Mcl-1 mediates its effects primarily through interactions with pro-apoptotic BH3 containing proteins that achieve high affinity for the target by utilizing four hydrophobic pockets in its binding groove. Here we describe the discovery of Mcl-1 inhibitors using fragment-based methods and structure-based design. These novel inhibitors exhibit low nanomolar binding affinities to Mcl-1 and >500-fold selectivity over Bcl-xL. X-ray structures of lead Mcl-1 inhibitors when complexed to Mcl-1 provided detailed information on how these small-molecules bind to the target and were used extensively to guide compound optimization.