SCH 529074 is a small molecule activator of p53, a tumor suppressor that is mutated or non-functional in 50% of human tumors. SCH 529074 restores DNA binding activity and increases DNA binding affinity of two recombinant GST fusion mutant p53 DNA binding domains (R273H and R249S) in an electrophoretic mobility shift assay with Kd values of 0.6740 and 0.4313, respectively. It also stimulates DNA binding activity and prevents human double minute-2 (Hdm-2) ubiquitination of wild-type p53 in vitro. SCH 29074 reduces proliferation of tumor cell lines with mutant and wild-type p53 (EC50s = 400-3,700 nM), with the p53 mutant cell lines being the most sensitive. In vivo, SCH 529074 reduces tumor growth in a DLD-1 human colorectal cancer xenograft model in mice in a dose-dependent manner.
