RITA and PRIMA-1 restore P53 Tumor Suppressor

[Rich66]

New Anti-Cancer Drugs Resurrect Mutant Tumor Suppressor 6/15/2009
For a malignant cell to emerge usually requires that it accumulate both activating mutations in pro-growth oncogenes and loss-of-function mutations in cancer-fighting tumor suppressors. Modern anti-cancer targeted therapeutics work by binding to and turning off key oncogenic proteins (usually signal transducing kinases) that drive tumor growth. Until now, scientists have had no way of fixing the broken tumor suppressor proteins that also contribute to cancer cell survival.
The p53 tumor suppressor is mutated into a functionally inert protein in the vast majority of human cancers. In healthy cells, p53 is a transcription factor that becomes activated in response to cellular stress (e.g., DNA damage) and turns on genes that lead to cell cycle arrest, senescence, and/or apoptosis. Loss of functional p53 allows tumor cells to evade p53-dependent arrest or cell death, and often contributes to chemoresistance. Hence, scientists have long speculated about potential strategies to restore the function of p53 in tumor cells.
Now researchers at the Karolinska Institute in Stockholm, Sweden, report two drugs called RITA and PRIMA-1 that reactivate mutant p53 and unleash its killing function in tumor cells. Experiments suggest that these drugs or their metabolites directly bind to and bend the mutated p53 protein back into its native conformation—a major achievement in medicinal chemistry.
Low doses of these p53-reactivating drugs greatly sensitized human tumor cells grown in culture or injected into mice to a variety of oncogene inhibitors and cytotoxic agents. These studies strongly suggest that tumor suppressors are “druggable” targets and that p53-selective compounds in particular represent a promising class of new anti-cancer agents. In fact, PRIMA-1 is currently being tested in a phase I clinical trial involving patients with refractory hematopoietic malignancies or prostate cancer.

Lambert JMR, Gorzov P, Veprintsev DB, et al.PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell. 2009;15:376-88.
Grinkevich VV, Nikulenkov F, Shi Y, et al. Ablation of key oncogenic pathways by RITA-reactivated p53 is required for efficient apoptosis. Cancer Cell. 2009;15:441-53.