基于片段的茶碱衍生物的设计、合成及作为 ATAD2 抑制剂在 BT-549 细胞中的生物评价。
Fragment-based design, synthesis and biological evaluation of theophylline derivatives as ATAD2 inhibitors in BT-549 cells.
机构信息
State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China.
School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen, China.
出版信息
J Enzyme Inhib Med Chem. 2023 Dec;38(1):2242601. doi: 10.1080/14756366.2023.2242601.
ATPase family AAA domain-containing protein 2 (ATAD2) has been emerging as a hot anti-cancer drugable target due to its oncogenic epigenetic modification closely associated with cancer cells proliferation, apoptosis, migration and drug resistance. In this study, we design a series of theophylline derivatives as novel ATAD2 inhibitors through fragment-based screening and scaffold growth strategy. A novel potent ATAD2 inhibitor (compound is discovered with an IC value of 0.27 μM against ATAD2, which adopts a combination of classic and atypical binding mode. Additionally, compound could impede ATAD2 activity and c-Myc activation, induced significant apoptosis, and illustrated an anti-migration effect in BT-549 cells. Collectively, these results provide new enlightenment for the development of novel potent ATAD2 inhibitors for triple-negative breast cancer (TNBC) treatment.
三磷酸腺苷酶家族 AAA 结构域包含蛋白 2（ATAD2）由于其与癌细胞增殖、凋亡、迁移和耐药性密切相关的致癌表观遗传修饰，已成为热门的抗癌药物靶点。在这项研究中，我们通过片段筛选和支架生长策略设计了一系列茶碱衍生物作为新型 ATAD2 抑制剂。我们发现了一种新型有效的 ATAD2 抑制剂（化合物 ），其对 ATAD2 的 IC 值为 0.27μM，采用了经典和非典型结合模式的结合。此外，化合物 可以抑制 ATAD2 活性和 c-Myc 激活，诱导 BT-549 细胞发生显著的凋亡，并表现出抗迁移作用。总的来说，这些结果为开发用于三阴性乳腺癌（TNBC）治疗的新型有效 ATAD2 抑制剂提供了新的启示。
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