tetracycline and maleimide

Reactivation of mutant p53 is likely to provide important benefits for treatment of chemotherapy- and radiotherapy-resistant tumors. We demonstrate here that the maleimide-derived molecule MIRA-1 can reactivate DNA binding and preserve the active conformation of mutant p53 protein in vitro and restore transcriptional transactivation to mutant p53 in living cells. MIRA-1 induced mutant p53-dependent cell death in different human tumor cells carrying tetracycline-regulated mutant p53. The structural analog MIRA-3 showed antitumor activity in vivo against human mutant p53-carrying tumor xenografts in SCID mice. The MIRA scaffold is a novel lead for the development of anticancer drugs specifically targeting mutant p53.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Separation; DNA; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Glutathione Transferase; Humans; Maleimides; Mice; Mice, SCID; Microscopy, Fluorescence; Models, Chemical; Mutation; Neoplasm Transplantation; Neoplasms; Plasmids; Protein Binding; Protein Conformation; Tetracycline; Transcriptional Activation; Tumor Suppressor Protein p53