更新于：2024-11-01

QPCT x GSK-3β

更新于：2024-11-01

基本信息

关联

项与 QPCT x GSK-3β 相关的药物

compound 8 (Shenzhen University )

靶点

GSK-3β x QPCT

作用机制

GSK-3β抑制剂 [+1]

在研机构

深圳大学

原研机构

深圳大学

在研适应症

阿尔茨海默症

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 QPCT x GSK-3β 相关的临床结果

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100 项与 QPCT x GSK-3β 相关的转化医学

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0 项与 QPCT x GSK-3β 相关的专利（医药）

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项与 QPCT x GSK-3β 相关的文献（医药）

2024-09-01·Bioorganic & Medicinal Chemistry Letters

Structure-activity relationship of dual inhibitors containing maleimide and imidazole motifs against glutaminyl cyclase and glycogen synthase kinase-3β

Article

作者: Wu, Haiqiang ; Cai, Jiaxin ; Xu, Chenshu ; Qin, Feixia ; Xiong, Wei ; Li, Chenyang ; Zhou, Qingqing ; Wei, Dingjun

Alzheimer's disease (AD) is a major cause of dementia and one of the most common chronic diseases affecting the aging population. Because AD is considered a public health priority, there is a critical need to discover novel and effective agents for the treatment of this condition. In view of the known contribution of up-regulated glutaminyl cyclase (QC) and glycogen synthase kinase-3β (GSK-3β) to the initiation of AD, we previously evaluated a series of dual inhibitors containing maleimide and imidazole motifs as potential anti-AD agents. Here, we assessed another series of hybrids containing maleimide and imidazole motifs to gain an in-depth understanding of the structure-activity relationship (SAR). Based on the primary screening, the introduction of 5-methyl imidazole at one side of the molecule did not enhance the QC-specific inhibitory activity of these hybrids (2, IC₅₀ = 1.22 μM), although the potency was increased by 2' substitution on the maleimide motif at the other side of the molecule. Interestingly, compounds containing 5-methyl imidazole exhibited stronger GSK-3β-specific inhibitory activity (2, IC₅₀ = 0.0021 μM), and the electron-withdrawing group and 2' and 3' substitution were favorable. Further investigation of substitutions on the maleimide motif in compounds 14-35 revealed that QC-specific inhibition in the presence of piperidine was improved by introduction of a methoxy group (R²). Increasing the linker length and introduction of a methoxy group (R²) also increased the GSK-3β-specific inhibitory potency. These findings were further confirmed by molecular docking analysis of 33 and 24 with QC and GSK-3β. Overall, these hybrids exhibited enhanced inhibitory potency against both QC and GSK-3β, highlighting an important strategy for improving the potency of hybrids as dual-targeting anti-AD agents.

2023-02-01·European Journal of Medicinal Chemistry

Design, synthesis and anti-AD effects of dual inhibitor targeting glutaminyl cyclase/GSK-3β

Article

作者: Ye, Shuixian ; Chen, Chen ; Ouyang, Na ; Xu, Chenshu ; Xie, Yazhou ; Wu, Haiqiang ; Li, Chenyang ; Yu, Xi ; Song, Guoli ; Lin, Shujing ; Chen, Xiaojie ; Xiong, Wei

Alzheimer's disease (AD), multifactorial disease, is recognized as one of the most common forms of dementia, and the efficacy of anti-AD drugs is limited clinically. Up-regulated glutaminyl cyclase (QC) and glycogen synthase kinase-3β (GSK-3β) have been identified as two critical elements involved in AD recently. Here, a series of novel chemicals containing maleimide and imidazole motif were designed and synthesized as dual inhibitors targeting QC and GSK-3β. Based on primary screening, compound 2 (2.26 μM), 5 (2.37 μM), 8 (1.34 μM), 21 (2.44 μM), 25 (0.36 μM), 27 (1.76 μM), 28 (1.04 μM), 33 (2.08 μM) and 34 (2.33 μM) exhibited notable human QC (hQC) inhibitory potency, while compound 1 (0.014 μM), 7 (0.04 μM), 8 (0.057 μM), 19 (0.034 μM), 24 (0.014 μM), 32 (0.032 μM), 38 (0.051 μM), 39 (0.044 μM), 44 (0.048 μM), 47 (0.011 μM), 49 (0.021 μM) and so on showed remarkable GSK-3β inhibitory activities. And as expected, these chemicals possessed significant inhibitory potency on both hQC and GSK-3β, such as compound 1 (2.80 and 0.014 μM), 8 (1.34 and 0.057 μM), 25 (0.36 and 0.15 μM), 27 (1.76 and 0.069 μM), 28 (1.04 and 0.090 μM), 33 (2.08 and 0.19 μM), 34 (2.33 and 0.11 μM), 35 (2.55 and 0.14 μM), 36 (2.34 and 0.11 μM), etc. Subsequent in vivo studies demonstrated that compound 8 attenuated cognitive deficits and decreased the anxiety-like behavior in 3 × Tg-AD mice. The treatment decreased both pE-Aβ and Aβ accumulation by inhibiting the activity of QC, and decreased the hyperphosphorylation of Tau by reducing the levels of GSK-3β in the brains of AD mice. Results obtained in this research suggested that these novel compounds could be supposed as potential anti-AD agents targeting QC and GSK-3β.

2013-02-01·Carcinogenesis2区 · 医学

Lycopene synergistically enhances quinacrine action to inhibit Wnt-TCF signaling in breast cancer cells through APC

2区 · 医学

Article

作者: Purusottam Mohapatra ; Michael D. Wyatt ; Dipon Das ; Tathagata Choudhuri ; Chanakya Nath Kundu ; Ranjan Preet ; Shakti Ranjan Satapathy

We previously reported that quinacrine (QC) has anticancer activity against breast cancer cells. Here, we examine the mechanism of action of QC and its ability to inhibit Wnt-TCF signaling in two independent breast cancer cell lines. QC altered Wnt-TCF signaling components by increasing the levels of adenomatous polyposis coli (APC), DAB2, GSK-3β and axin and decreasing the levels of β-catenin, p-GSK3β (ser 9) and CK1. QC also reduced the activity of the Wnt transcription factor TCF/LEF and its downstream targets cyclin D1 and c-MYC. Using a luciferase-based Wnt-TCF transcription factor assay, it was shown that APC levels were inversely associated with TCF/LEF activity. Induction of apoptosis and DNA damage was observed after treatment with QC, which was associated with increased expression of APC. The effects induced by QC depend on APC because the inhibition of Wnt-TCF signaling by QC is lost in APC-knockdown cells, and consequently, the extent of apoptosis and DNA damage caused by QC is reduced compared with parental cells. Because we previously showed that QC inhibits topoisomerase, we examined the effect of another topoisomerase inhibitor, etoposide, on Wnt signaling. Interestingly, etoposide treatment also reduced TCF/LEF activity, β-catenin and cyclin D1 levels commensurate with induction of DNA damage and apoptosis. Lycopene, a plant-derived antioxidant, synergistically increased QC activity and inhibited Wnt-TCF signaling in cancer cells without affecting the MCF-10A normal breast cell line. Collectively, the data suggest that QC-mediated Wnt-TCF signal inhibition depends on APC and that the addition of lycopene synergistically increases QC anticancer activity.