Antitumor effect of novel small chemical inhibitors of Snail-p53 binding in K-Ras-mutated cancer cells

Abstract

p53 is frequently mutated by genetic alternation or suppressed by various kinds of cellular signaling pathways in human cancers. Recently, we have revealed that p53 is suppressed and eliminated from cells by direct binding with oncogenic K-Ras-induced Snail. On the basis of the fact, we generated specific inhibitors against p53-Snail binding (GN25 and GN29). These chemicals can induce p53 expression and functions in K-Ras-mutated cells. However, it does not show cytotoxic effect on normal cells or K-Raswild- type cells. Moreover, GN25 can selectively activate wild-type p53 in p53(WT/MT) cancer cells. But single allelic mt p53 containing cell line, Panc-1, does not respond to our chemical. In vivo xenograft test also supports the antitumor effect of GN25 in K-Ras-mutated cell lines. These results suggest that our compounds are strong candidate for anticancer drug against K-Ras-initiated human cancers including pancreatic and lung cancers. Oncogene (2010) 29, 4576-4587; doi: 10.1038/onc.2010.208; published online 7 June 2010