Structure-activity relationship studies of QS11, a small molecule Wnt synergistic agonist.
Structure-activity relationship studies of QS11, a small molecule Wnt synergistic agonist.
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DOI：
10.1016/j.bmcl.2015.06.062
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发表时间：
2015-11-01
影响因子：
2.7
通讯作者：
Zhang Q
中科院分区：
文献类型：
--
作者：
Singh MK;Gao H;Sun W;Song Z;Schmalzigaug R;Premont RT;Zhang Q
Wnt/β-连环蛋白信号通路和 ADP-核糖基化因子 (ARF) 家族的小 GTP 酶在调节细胞发育、稳态和命运中发挥着重要作用。 QS11 是一种与 ARF GTP 酶激活蛋白 1 (ARFGAP1) 结合的小分子 Wnt 增效剂，之前的报道表明 ARFGAP1 在 Wnt/β-catenin 通路中发挥作用。然而，QS11 对 ARFGAP1 酶活性的直接抑制尚未确定。 ARFGAP1 是否是 QS11 的 Wnt 协同作用的唯一靶点也尚不清楚。在这里，我们通过两种测定法对 QS11 类似物进行构效关系 (SAR) 研究：直接抑制纯化的 ARFGAP1 蛋白的酶活性和细胞激活 Wnt/β-catenin 通路。结果证实了 QS11 对 ARFGAP1 的直接抑制，并且还表明 QS11 存在其他潜在的细胞靶标。
Both the Wnt/β-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/β-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/β-catenin pathway. The results confirm the direct inhibition of ARFGAP1 by QS11, and also suggest the presence of other potential cellular targets of QS11.