Since p53 is the strongest tumor suppressor gene, which can regulate apoptosis, cell cycle arrest and senescence, re-activation of p53 and its pathway seem to be very plausible target for cancer therapy. However, in 50% of human cancers, p53 itself is mutated. In addition, in remaining half of cancers, it is inactivated by distortion of signaling pathways. Moreover, differentially from typical tumor suppressor genes such as Rb, p53 mutations in its DNA binding domain show the dominant negative effect on p53 function. Here, we describe the novel p53 inactivation mechanism by oncogenic K-Ras-Snail axis and smart strategy to reactivation of p53 suppressed by oncogenic K-Ras-Snail through small chemicals (GN25, 29). Since K-Ras mutation is frequently occurred in human pancreatic, colon, and lung cancer, we discuss the clinical implication of new small Snail-p53 inhibitor on these cancers. In addition, we suggest possibility of reactivation of wild type p53, governed by mutant p53, is suggested using our chemicals. Through this, we will provide the new strategy to handling the K-Ras mutated human cancers including pancreatic, lung and colon cancers.