SIRT6 promotes the progression of breast cancer by inducing drug resistance by reinforcing DNA damage repair mechanisms. This study utilized a combination of high-throughput virtual screening and FLUOR DE LYS assays. Hit 14 which features a novel β-carboline skeleton as a potent SIRT6 inhibitor was found. Subsequent structure-guided optimization led to the synthesis of 60 3,6,9-position modified derivatives based on the differences analysis of SIRTs family proteins. Of which, 10d inhibited the deacetylase activity of SIRT6, with an IC₅₀ of 5.81 μM and more than 27 times subtype selectivity. Phe64, Met157, and Ser56 were identified as the key residues. Moreover, 10d suppressed breast cancer cell proliferation, migration, invasion, and induced apoptosis in MCF-7 cells by disrupting the DNA damage repair pathway. Additionally, 10d demonstrated a safe and effective antibreast cancer effect in vivo, presenting a promising strategy for the treatment of breast cancer by targeting SIRT6.

中文翻译：

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结构引导发现具有 β-Carboline 骨架的亚型选择性 SIRT6 抑制剂治疗乳腺癌


SIRT6 通过增强 DNA 损伤修复机制诱导耐药性，从而促进乳腺癌的进展。本研究结合了高通量虚拟筛选和 FLUOR DE LYS 检测。发现 Hit 14 具有新型 β-咔啉骨架作为有效的 SIRT6 抑制剂。随后的结构引导优化导致基于 SIRTs 家族蛋白的差异分析合成了 60 个 3,6,9 位修饰衍生物。其中，10d 抑制 SIRT6 的脱乙酰酶活性，IC₅₀ 为 5.81 μM，亚型选择性是亚型选择性的 27 倍以上。Phe64 、 Met157 和 Ser56 被鉴定为关键残基。此外，10d 通过破坏 DNA 损伤修复途径抑制乳腺癌细胞增殖、迁移、侵袭并诱导 MCF-7 细胞凋亡。此外，10d 在体内显示出安全有效的抗乳腺癌作用，通过靶向 SIRT6 为治疗乳腺癌提供了一种有前途的策略。