Liang Chaowei, Wang Siyu, Feng Dongyan, Wang Shenglin, Zheng Chao, Qu Ying, Wang Weirenbo, Ma Yongzhi, Li Haonan, Yang Hangao, Cao Hao, Hua Huiming, Cheng Maosheng, Li Dahong
Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, P. R. China.
School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, P. R. China.
J Med Chem. 2024 Dec 26;67(24):21975-22001. doi: 10.1021/acs.jmedchem.4c01921. Epub 2024 Dec 4.
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. 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, inhibited the deacetylase activity of SIRT6, with an IC of 5.81 μM and more than 27 times subtype selectivity. Phe64, Met157, and Ser56 were identified as the key residues. Moreover, suppressed breast cancer cell proliferation, migration, invasion, and induced apoptosis in MCF-7 cells by disrupting the DNA damage repair pathway. Additionally, demonstrated a safe and effective antibreast cancer effect , presenting a promising strategy for the treatment of breast cancer by targeting SIRT6.
SIRT6通过加强DNA损伤修复机制诱导耐药性，从而促进乳腺癌的进展。本研究采用了高通量虚拟筛选和FLUOR DE LYS分析相结合的方法。发现了一种具有新型β-咔啉骨架的强效SIRT6抑制剂。随后基于SIRTs家族蛋白的差异分析，通过结构导向优化合成了60种3、6、9位修饰的衍生物。其中，抑制了SIRT6的去乙酰化酶活性，IC为5.81μM，亚型选择性超过27倍。确定Phe64、Met157和Ser56为关键残基。此外，通过破坏DNA损伤修复途径，抑制了MCF-7细胞中乳腺癌细胞的增殖、迁移、侵袭并诱导其凋亡。此外，显示出安全有效的抗乳腺癌作用，为靶向SIRT6治疗乳腺癌提供了一种有前景的策略。
