anti-cancer activity of a novel small molecule compound that simultaneously activates p53 and inhibits nf-κb signaling抗癌活性的新型小分子化合物,同时激活p53和抑制nf-κb信号.pdfVIP

Anti-Cancer Activity of a Novel Small Molecule Compound That Simultaneously Activates p53 and Inhibits NF-kB Signaling 1,2 3 1 1 1 1 Sun Gwan Hwang , Jinah Park , Joo Young Park , Cheol Hyoung Park , Ki-Ho Lee , Jeong Woo Cho , 2 2 Jong-Ik Hwang , Jae Young Seong * 1 Drug Development Center, SK Biopharmaceuticals Co., Ltd., Daejeon, Korea, 2 Laboratory of G Protein Coupled Receptors, Graduate School of Medicine Korea University, Seoul, Korea, 3 Korean Bioinformation Center, KRIBB, Daejeon, Korea Abstract The p53 and NF-kB pathways play important roles in diverse cellular functions, including cell growth, apoptosis, and tumorigenesis. Mutations that inactivate the p53 gene and constitutive NF-kB pathway activation are common occurrences in human cancers. Although many drugs are being developed that selectively activate p53 or inhibit NF-kB, there are few drug candidates that can do both. Simultaneous activation of p53 and inhibition of the NF-kB pathway is therefore a prime target for new cancer drug development. This study is the first report of a high-throughput approach with mass compounds that concurrently target both pathways. Using a cell-based screening assay and a library of 200,000 synthetic compounds, we identified 9 small molecules that simultaneously inhibit NF-kB and activate p53. One of these compounds, N-2, increased the expression of p53 target genes, including p21 and GADD45a. In addition, N-2 inhibited the transcriptional activity of NF- kB, concomitantly repressing interleukin-6 and monocyte chemotactic protein-1 (MCP-1) expression. When cell lines derived from a diverse range of cancers were treated in vitro with N-2, we ob