Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs.
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.
Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Stockholm, Sweden.
Vladimir J N
VJ
Bykov
Natalia
N
Issaeva
Nicole
N
Zache
Alexandre
A
Shilov
Monica
M
Hultcrantz
Jan
J
Bergman
Galina
G
Selivanova
Klas G
KG
Wiman
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002469:Cell Separation; D004247:DNA / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008301:Maleimides / Q000494:pharmacology*; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D008956:Models, Chemical; D009154:Mutation; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D013752:Tetracycline / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*
D000970:Antineoplastic Agents; D008301:Maleimides; D016159:Tumor Suppressor Protein p53; C043592:maleimide; D004247:DNA; D005982:Glutathione Transferase; D013752:Tetracycline