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Discovery of Novel N-(Anthracen-9-ylmethyl) Benzamide Derivatives as ZNF207 Inhibitors Promising in Treating Glioma
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-02-20 , DOI: 10.1021/acs.jmedchem.3c02241 Menghan Zhang 1 , Yushi Ding 2 , Mengkang Gao 3 , Xiaolin Lu 4 , Jun Tan 4 , Fei Yu 1 , Congying Gu 4 , Lujun Gu 1 , Xiameng Ren 1 , Chenyan Hao 4 , Liqin Ming 4 , Kang Xu 4 , Wenhao Mao 1 , Yuqing Jin 1 , Min Zhang 2 , Linjun You 2, 5 , Zhanbo Wang 2, 5 , Yuanyuan Sun 6 , Jingwei Jiang 6 , Yong Yang 1, 7, 8 , Dayong Zhang 4 , Xinying Tang 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-02-20 , DOI: 10.1021/acs.jmedchem.3c02241 Menghan Zhang 1 , Yushi Ding 2 , Mengkang Gao 3 , Xiaolin Lu 4 , Jun Tan 4 , Fei Yu 1 , Congying Gu 4 , Lujun Gu 1 , Xiameng Ren 1 , Chenyan Hao 4 , Liqin Ming 4 , Kang Xu 4 , Wenhao Mao 1 , Yuqing Jin 1 , Min Zhang 2 , Linjun You 2, 5 , Zhanbo Wang 2, 5 , Yuanyuan Sun 6 , Jingwei Jiang 6 , Yong Yang 1, 7, 8 , Dayong Zhang 4 , Xinying Tang 1
Affiliation
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Targeting tumor stemness is an innovative approach to cancer treatment. Zinc Finger Protein 207 (ZNF207) is a promising target for weakening the stemness of glioma cells. Here, a series of novel N-(anthracen-9-ylmethyl) benzamide derivatives against ZNF207 were rationally designed and synthesized. The inhibitory activity was evaluated, and their structure–activity relationships were summarized. Among them, C16 exhibited the most potent inhibitory activity, as evidenced by its IC50 values ranging from 0.5–2.5 μM for inhibiting sphere formation and 0.5–15 μM for cytotoxicity. Furthermore, we found that C16 could hinder tumorigenesis and migration and promote apoptosis in vitro. These effects were attributed to the downregulation of stem-related genes. The in vivo evaluation demonstrated that C16 exhibited efficient permeability across the blood–brain barrier and potent efficacy in both subcutaneous and orthotopic glioma tumor models. Hence, C16 may serve as a potential lead compound targeting ZNF207 and has promising therapeutic potential for glioma.
中文翻译：
发现新型 N-(蒽-9-基甲基) 苯甲酰胺衍生物作为 ZNF207 抑制剂，有望治疗胶质瘤
针对肿瘤干性是一种创新的癌症治疗方法。锌指蛋白 207 (ZNF207) 是削弱神经胶质瘤细胞干性的一个有前景的靶点。在此，合理设计并合成了一系列针对ZNF207的新型N- (蒽-9-基甲基)苯甲酰胺衍生物。评估了抑制活性，并总结了它们的构效关系。其中， C16表现出最有效的抑制活性，其抑制球体形成的 IC 50值范围为 0.5-2.5 μM，抑制细胞毒性的 IC 50 值范围为 0.5-15 μM。此外，我们发现C16在体外可以阻碍肿瘤的发生和迁移并促进细胞凋亡。这些影响归因于干相关基因的下调。体内评估表明， C16表现出有效的血脑屏障渗透性，并且在皮下和原位神经胶质瘤模型中具有强大的功效。因此， C16可能作为靶向 ZNF207 的潜在先导化合物，对神经胶质瘤具有良好的治疗潜力。
更新日期：2024-02-20
中文翻译：
发现新型 N-(蒽-9-基甲基) 苯甲酰胺衍生物作为 ZNF207 抑制剂，有望治疗胶质瘤
针对肿瘤干性是一种创新的癌症治疗方法。锌指蛋白 207 (ZNF207) 是削弱神经胶质瘤细胞干性的一个有前景的靶点。在此，合理设计并合成了一系列针对ZNF207的新型N- (蒽-9-基甲基)苯甲酰胺衍生物。评估了抑制活性，并总结了它们的构效关系。其中， C16表现出最有效的抑制活性，其抑制球体形成的 IC 50值范围为 0.5-2.5 μM，抑制细胞毒性的 IC 50 值范围为 0.5-15 μM。此外，我们发现C16在体外可以阻碍肿瘤的发生和迁移并促进细胞凋亡。这些影响归因于干相关基因的下调。体内评估表明， C16表现出有效的血脑屏障渗透性，并且在皮下和原位神经胶质瘤模型中具有强大的功效。因此， C16可能作为靶向 ZNF207 的潜在先导化合物，对神经胶质瘤具有良好的治疗潜力。
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