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Exploring Marine-Derived Ascochlorins as Novel Human Dihydroorotate Dehydrogenase Inhibitors for Treatment of Triple-Negative Breast Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-09-13 , DOI: 10.1021/acs.jmedchem.1c01402 Xiaowei Luo 1 , Guodi Cai 2 , Yinfeng Guo 2 , Chenghai Gao 1 , Weifeng Huang 2 , Zhenhua Zhang 2 , Humu Lu 1 , Kai Liu 1 , Jianghe Chen 2 , Xiaofeng Xiong 2 , Jinping Lei 2 , Xuefeng Zhou 3, 4 , Junjian Wang 2 , Yonghong Liu 1, 3, 4
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-09-13 , DOI: 10.1021/acs.jmedchem.1c01402 Xiaowei Luo 1 , Guodi Cai 2 , Yinfeng Guo 2 , Chenghai Gao 1 , Weifeng Huang 2 , Zhenhua Zhang 2 , Humu Lu 1 , Kai Liu 1 , Jianghe Chen 2 , Xiaofeng Xiong 2 , Jinping Lei 2 , Xuefeng Zhou 3, 4 , Junjian Wang 2 , Yonghong Liu 1, 3, 4
Affiliation
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Human dihydroorotate dehydrogenase (hDHODH) is an attractive tumor target essential to de novo pyrimidine biosynthesis. Novel potent hDHODH inhibitors with low toxicity are urgently needed. Herein, we demonstrate the isolation of 25 ascochlorin (ASC) derivatives, including 13 new ones, from the coral-derived fungus Acremonium sclerotigenum, and several of them showed pronounced inhibitions against hDHODH and triple-negative breast cancer (TNBC) cell lines, MDA-MB-231/-468. Interestingly, we found that hDHODH is required for proliferation and survival of TNBC cells, and several ASCs significantly inhibited TNBC cell growth and induced their apoptosis via hDHODH inhibition. Furthermore, the novel and potent hDHODH inhibitors (1 and 21) efficiently suppressed tumor growth in patient-derived TNBC xenograft models without obvious body weight loss or overt toxicity in mice. Collectively, our findings offered a novel lead scaffold as the hDHODH inhibitor for further development of potent anticancer agents and a potential therapeutic strategy for TNBC.
中文翻译：
探索海洋衍生的壳二酚作为新型人二氢乳清酸脱氢酶抑制剂治疗三阴性乳腺癌
人二氢乳清酸脱氢酶 ( h DHODH) 是嘧啶从头生物合成所必需的有吸引力的肿瘤靶标。迫切需要低毒的新型强效h DHODH 抑制剂。在此，我们展示了从珊瑚来源的真菌Acremium scleotigenum中分离出 25 种壳二酚 (ASC) 衍生物，包括 13 种新衍生物，其中几种对h DHODH 和三阴性乳腺癌 (TNBC) 细胞系表现出明显的抑制作用， MDA-MB-231/-468。有趣的是，我们发现h DHODH 是 TNBC 细胞增殖和存活所必需的，并且一些 ASC 显着抑制 TNBC 细胞生长，并通过抑制h DHODH 诱导其凋亡。此外，新型有效的h DHODH 抑制剂（ 1和21 ）可有效抑制患者来源的 TNBC 异种移植模型中的肿瘤生长，且小鼠体内没有明显的体重减轻或明显的毒性。总的来说，我们的研究结果提供了一种新型的先导支架作为h DHODH 抑制剂，用于进一步开发有效的抗癌药物和 TNBC 的潜在治疗策略。
更新日期：2021-09-23
中文翻译：
探索海洋衍生的壳二酚作为新型人二氢乳清酸脱氢酶抑制剂治疗三阴性乳腺癌
人二氢乳清酸脱氢酶 ( h DHODH) 是嘧啶从头生物合成所必需的有吸引力的肿瘤靶标。迫切需要低毒的新型强效h DHODH 抑制剂。在此，我们展示了从珊瑚来源的真菌Acremium scleotigenum中分离出 25 种壳二酚 (ASC) 衍生物，包括 13 种新衍生物，其中几种对h DHODH 和三阴性乳腺癌 (TNBC) 细胞系表现出明显的抑制作用， MDA-MB-231/-468。有趣的是，我们发现h DHODH 是 TNBC 细胞增殖和存活所必需的，并且一些 ASC 显着抑制 TNBC 细胞生长，并通过抑制h DHODH 诱导其凋亡。此外，新型有效的h DHODH 抑制剂（ 1和21 ）可有效抑制患者来源的 TNBC 异种移植模型中的肿瘤生长，且小鼠体内没有明显的体重减轻或明显的毒性。总的来说，我们的研究结果提供了一种新型的先导支架作为h DHODH 抑制剂，用于进一步开发有效的抗癌药物和 TNBC 的潜在治疗策略。
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