Structure-Guided Discovery of Subtype Selective SIRT6 Inhibitors with a β-Carboline Skeleton for the Treatment of Breast Cancer

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. <b>Hit 14</b> 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, <b>10d</b> 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, <b>10d</b> suppressed breast cancer cell proliferation, migration, invasion, and induced apoptosis in MCF-7 cells by disrupting the DNA damage repair pathway. Additionally, <b>10d</b> demonstrated a safe and effective antibreast cancer effect <i>in vivo</i>, presenting a promising strategy for the treatment of breast cancer by targeting SIRT6.