Pharmacological rescue of mutant p53 conformation and function.
Compounds that stabilize the DNA binding domain of p53 in the active conformation were identified. These small synthetic molecules not only promoted the stability of wild-type p53 but also allowed mutant p53 to maintain an active conformation. A prototype compound caused the accumulation of conformationally active p53 in cells with mutant p53, enabling it to activate transcription and to slow tumor growth in mice. With further work aimed at improving potency, this class of compounds may be developed into anticancer drugs of broad utility.
Foster
B A
BA
Department of Genomics, Targets, and Cancer Research, Pfizer Central Research, Eastern Point Road, Groton, CT 06340, USA.
Coffey
H A
HA
Morin
M J
MJ
Rastinejad
F
F
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004247:DNA / Q000378:metabolism; D000939:Epitopes; D016158:Genes, p53; D006801:Humans; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013696:Temperature; D014158:Transcription, Genetic; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D000939:Epitopes; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; D004247:DNA; C402665:CP 31398