Awakening guardian angels: drugging the p53 pathway.
Currently, around 11 million people are living with a tumour that contains an inactivating mutation of TP53 (the human gene that encodes p53) and another 11 million have tumours in which the p53 pathway is partially abrogated through the inactivation of other signalling or effector components. The p53 pathway is therefore a prime target for new cancer drug development, and several original approaches to drug discovery that could have wide applications to drug development are being used. In one approach, molecules that activate p53 by blocking protein-protein interactions with MDM2 are in early clinical development. Remarkable progress has also been made in the development of p53-binding molecules that can rescue the function of certain p53 mutants. Finally, cell-based assays are being used to discover compounds that exploit the p53 pathway by either seeking targets and compounds that show synthetic lethality with TP53 mutations or by looking for non-genotoxic activators of the p53 response.
Brown
Christopher J
CJ
p53 Laboratory (A-STAR), 8A Biomedical Grove, Immunos, Singapore 138648.
Lain
Sonia
S
Verma
Chandra S
CS
Fersht
Alan R
AR
Lane
David P
DP
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D016503:Drug Delivery Systems; D015195:Drug Design; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000819:agonists* / Q000378:metabolism
D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2