基于片段的设计、合成和生物评价来研发茶碱衍生物作为BT-549细胞中ATAD2抑制剂。
Fragment-based design, synthesis and biological evaluation of theophylline derivatives as ATAD2 inhibitors in BT-549 cells.
发表日期：2023 Dec
作者：
Dahong Yao, Jieshu You, Xuetao Yang, Jin Zhang, Xiaojun Yao
来源：
Epigenetics & Chromatin
摘要：
ATPase AAA领域含2的蛋白(ATAD2)已逐渐成为热门的抗癌药物靶点，因其与癌细胞增殖、凋亡、迁移和药物抗性密切相关的癌基因表观遗传修饰。本研究通过基于片段筛选和支架生长策略设计了一系列新型ATAD2抑制剂的茶碱衍生物。发现了一种新的ATAD2抑制剂(化合物19f)，其对ATAD2的IC50值为0.27 μM，采用了经典和非经典结合模式的组合。此外，化合物19f可阻碍ATAD2活性和c-Myc的激活，诱导显著的凋亡，并在BT-549细胞中显示出抗迁移作用。综上，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。
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 19f) is discovered with an IC50 value of 0.27 μM against ATAD2, which adopts a combination of classic and atypical binding mode. Additionally, compound 19f 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.