Discovery of novel SIRT3 inhibitors with MLLr leukemia inhibitory potency

SIRT3 has emerged as a therapeutic target for the treatment of leukemia. Based on our previously identified lead compound, structural modification was performed in the current study. A total of 20 compounds were designed and synthesized. In the enzymatic inhibitory assay, compounds C19 and C20 exhibited SIRT3 inhibitory activity and selectivity. Significantly, compounds C19 and C20 showed in vitro anticancer activity with IC₅₀ values of 0.54 μM and 0.41 μM against MOLM-13 cells, and with IC₅₀ values of 0.36 μM and 0.27 μM against MV4-11 cells, respectively. In the colony formation test, compound C20 effectively inhibited the growth and colony forming ability of MOLM-13 and MV4-11 cells. Cell cycle analysis revealed that compound C20 induced G0/G1 phase cell cycle arrest of MOLM-13 cells and S phase cell cycle arrest of MV4-11 cells, respectively. Additionally, compound C20 promoted apoptosis of MOLM-13 and MV4-11 cells in a dose dependent manner, as demonstrated by apoptotic analysis. Collectively, a SIRT3 selective inhibitor with MLLr leukemic cell inhibitory activities was derived for further structural optimization.