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Inhibition of SIRT3 exhibited potency in triggering leukemic cell differentiation. In discovery of potent SIRT3 inhibitors for cancer differentiation therapy, structural modification was performed on the previously developed lead compound P6. A total of 33 compounds were designed and synthesized. In the enzyme inhibitory assay, several molecules S18, S26, S27 and T5 showed potent SIRT3 inhibitory activity with IC50 value of 0.53, 1.86, 5.06, and 2.88 μM, respectively. Moreover, the tested compounds exhibited SIRT3 inhibitory selectivity over SIRT1 and SIRT2. Compounds S27 and T5 were potent in inhibition the growth of MM1.S and RPMI‐8226 cells in the in vitro antiproliferative test. Significantly, representative compounds, especially S27 and T5, promoted differentiation of tested MM cells in the cellular morphological evaluation, accompanied by increasing the expression of differentiation antigen CD49e and human immunoglobulin light chain lambda and kappa. Additionally, molecule S18 without antiproliferative potency itself, showed significant inhibitory activity against growth factor IL‐6 induced RPMI‐8226 cell proliferation. Collectively, potent SIRT3 selective inhibitors with MM cell differentiation potency were developed for further discovery of anticancer drugs. [ABSTRACT FROM AUTHOR]

Summary: Cold stress is a major limiting factor in grape (Vitis) productivity. In this study, we characterized a cold‐responsive ethylene response factor (ERF) transcription factor, VaERF092, from Amur grape (Vitis amurensis). VaERF092 expression was induced by both low temperatures and the ethylene precursor 1‐aminocyclopropane‐1‐carboxylate (ACC), but was suppressed by treatment with the ethylene inhibitor aminoethoxyvinylglycine (AVG) under cold conditions. Ectopic expression of VaERF092 in Arabidopsis thaliana enhanced cold tolerance. Co‐expression network analysis of V. vinifera genes indicated that WRKY33 might be a downstream target of VaERF092. This hypothesis was supported by the fact that VaWRKY33 was expressed temporally after VaERF092 expression and could also be induced by cold and ACC, and inhibited by AVG. Yeast one‐hybrid, transient β‐glucuronidase (GUS) and dual‐luciferase reporter assays provided evidence for an interaction between VaERF092 and a GCC‐box element in the VaWRKY33 promoter. In addition, heterologous overexpression of VaWRKY33 in A. thaliana resulted in enhanced cold tolerance. VaERF092‐ and VaWRKY33 overexpressing grape calli showed lower low‐temperature exothermic values than the empty vector (EV) calli, indicating enhanced tolerance to cold. Together, these results indicated that VaERF092 regulates VaWRKY33 through binding to its promoter GCC‐box, leading to enhanced cold stress tolerance. Significance Statement: Our study revealed that ethylene response factor VaERF092 regulated VaWRKY33 through binding to its promoter GCC‐box, leading to enhanced cold tolerance. This finding may provide a model responding to cold stress in plants. [ABSTRACT FROM AUTHOR]