Restoring p53-dependent tumor suppression.
p53 represents an ideal target for anti-cancer drug design, because p53 is mutated in more than half of human tumors. Most of the remaining tumors, although carrying wild-type p53, have defects in the p53-mediated apoptotic pathway. Activation of p53 activity by either chemotherapy or radiotherapy induces p53-dependent apoptosis in tumor cells with wild-type p53. Supplying exogenous wild-type p53 in cancer cells by gene delivery is effective in suppressing tumor growth of both mutant and wild-type p53-containing tumors. Blockage of p53 degradation pathways either by overexpression of ARF or interruption of MDM2:p53 interaction is effective in inducing p53 triggered tumor cell death. Since unlike most other tumor suppressor genes, mutant p53 is over expressed in tumor cells, a promising approach involves restoring tumor-suppressing function to mutant p53. The activity of the mutant p53 in tumor cells is restorable based on the fact that PAb241 antibody against the carboxy-terminus of p53 and peptides corresponding to the p53 carboxy-terminus can restore specific DNA-binding ability to some mutant p53 proteins. High throughout screening of chemical libraries has led to the identification of a group of small synthetic molecules such as CP-31398, which can restore p53 function to mutant p53 by stabilizing the active conformation of the protein that is destabilized in many mutants. Subsequent identification of PRIMA-1 provides further evidence to the possibility of developing anti-cancer drugs that may rescue mutant p53. Further understanding of the mechanisms by which CP-31398 and PRIMA-1 restore p53 activity may not only lead to discovery of more potent analogs but may also suggest new strategies for p53-targeting in tumor therapy.
D000970:Antineoplastic Agents / Q000494:pharmacology; D001372:Aza Compounds / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D006801:Humans; D008954:Models, Biological; D008956:Models, Chemical; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000628:therapy*; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation; D011743:Pyrimidines / Q000494:pharmacology; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000970:Antineoplastic Agents; D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010455:Peptides; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; C451219:2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one; C402665:CP 31398