Discovery of Potent Mcl-1/Bcl-xL Dual Inhibitors by Using a Hybridization Strategy Based on Structural Analysis of Target Proteins

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• 作者：Yuta Tanaka ; Katsuji Aikawa ; Goushi Nishida ; Misaki Homma ; Satoshi Sogabe ; Shigeru Igaki ; Yumi Hayano ; Tomoya Sameshima ; Ikuo Miyahisa ; Tomohiro Kawamoto ; Michiko Tawada ; Yumi Imai ; Masakazu Inazuka ; Nobuo Cho ; Yasuhiro Imaeda ; Tomoyasu Ishikawa
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：December 12, 2013
• 年：2013
• 卷：56
• 期：23
• 页码：9635-9645
• 全文大小：641K
• 年卷期：v.56,no.23(December 12, 2013)
• ISSN：1520-4804

文摘

Mcl-1 and Bcl-xL are crucial regulators of apoptosis, therefore dual inhibitors of both proteins could serve as promising new anticancer drugs. To design Mcl-1/Bcl-xL dual inhibitors, we performed structure-guided analyses of the corresponding selective Mcl-1 and Bcl-xL inhibitors. A cocrystal structure of a pyrazolo[1,5-a]pyridine derivative with Mcl-1 protein was successfully determined and revealed the protein鈥搇igand binding mode. The key structure for Bcl-xL inhibition was further confirmed through the substructural analysis of ABT-263, a representative Bcl-xL/Bcl-2/Bcl-w inhibitor developed by Abbott Laboratories. On the basis of the structural data from this analysis, we designed hybrid compounds by tethering the Mcl-1 and Bcl-xL inhibitors together. The results of X-ray crystallographic analysis of hybrid compound 10 in complexes with both Mcl-1 and Bcl-xL demonstrated its binding mode with each protein. Following further optimization, compound 11 showed potent Mcl-1/Bcl-xL dual inhibitory activity (Mcl-1, IC₅₀ = 0.088 渭M; and Bcl-xL, IC₅₀ = 0.0037 渭M).