Structure-activity relationship studies of QS11, a small molecule Wnt synergistic agonist

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• 作者：Manish K. Singh^a ; ^&dagger ; ; Huanyao Gao^a ; ^&dagger ; ; Wei Sun^a ; ^&dagger ; ; Zhiquan Song^a ; Robert Schmalzigaug^b ; Richard T. Premont^b ; Qisheng Zhang^a ; ^{qszhang@unc.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Wnt/尾-catenin signaling ; ADP-ribosylation factors ; GTPase-activating proteins ; QS11 ; Structure&ndash ; activity relationship (SAR)
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：1 November 2015
• 年：2015
• 卷：25
• 期：21
• 页码：4838-4842
• 全文大小：4801 K

文摘

Both the Wnt/尾-catenin signaling pathway and small GTPases of the ADP-ribosylation factors (ARF) family play important roles in regulating cell development, homeostasis and fate. The previous report of QS11, a small molecule Wnt synergist that binds to ARF GTPase-activating protein 1 (ARFGAP1), suggests a role for ARFGAP1 in the Wnt/尾-catenin pathway. However, direct inhibition of enzymatic activity of ARFGAP1 by QS11 has not been established. Whether ARFGAP1 is the only target that contributes to QS11’s Wnt synergy is also not clear. Here we present structure–activity relationship (SAR) studies of QS11 analogs in two assays: direct inhibition of enzymatic activity of purified ARFGAP1 protein and cellular activation of the Wnt/尾-catenin pathway. The results confirm the direct inhibition of ARFGAP1 by QS11, and also suggest the presence of other potential cellular targets of QS11.