Abstract

ATAD2 has been reported to play an important role in the processes of numerous cancers and validated to be a potential therapeutic target. This work is to discover potent ATAD2 inhibitors and elucidate the underlying mechanisms in breast cancer. A novel ATAD2 bromodomain inhibitor (AM879) was discovered by combining structure-based virtual screening with biochemical analyses. AM879 presents potent inhibitory activity towards ATAD2 bromodomain (IC₅₀ = 3565 nM), presenting no inhibitory activity against BRD2-4. Moreover, AM879 inhibited MDA-MB-231 cells proliferation with IC₅₀ value of 2.43 µM, suppressed the expression of c-Myc, and induced significant apoptosis. Additionally, AM978 could induce autophagy via PI3K-AKT-mTOR signalling in MDA-MB-231 cells. This study demonstrates the development of potent ATAD2 inhibitors with novel scaffolds for breast cancer therapy.

摘要

据报道，ATAD2在许多癌症的过程中起着重要作用，并被证实是潜在的治疗靶标。这项工作是发现有效的ATAD2抑制剂并阐明乳腺癌的潜在机制。通过将基于结构的虚拟筛选与生化分析相结合，发现了一种新型的ATAD2溴结构域抑制剂（AM879）。AM879对ATAD2溴结构域表现出有效的抑制活性（IC ₅₀ = 3565 nM），对BRD2-4没有抑制活性。此外，AM879通过IC ₅₀抑制MDA-MB-231细胞增殖值2.43μM，抑制c-Myc的表达，并诱导明显的细胞凋亡。此外，AM978可以通过MDA-MB-231细胞中的PI3K-AKT-mTOR信号诱导自噬。这项研究证明了新型乳腺癌支架的有效ATAD2抑制剂的开发。