More than 50% of human tumours carry mutations in TP53 , so strategies to restore the activity of this tumour suppressor in cancer cells are being actively investigated by drug companies. A team of researchers in Sweden and Russia now report the discovery of a compound that reactivates p53 function and induces apoptosis in human cancer cells.

In the March issue of Nature Medicine, Bykov et al. describe a chemical library screen for compounds that selectively inhibit the growth of mutant TP53-expressing tumour cells. This led to the discovery of a small molecule that they called PRIMA-1 (p53 reactivation and induction of massive apoptosis), which inhibits the growth of cells expressing a number of different TP53 mutations. p53 is a transcription factor that suppresses tumour growth by several mechanisms, including induction of apoptosis. Bykov et al. show that treatment of tumour cells with PRIMA-1 caused a substantial increase in the number of cells undergoing caspase-mediated apoptosis. Furthermore, growth of tumours that carry p53 mutations was suppressed in mouse xenografts following both intratumoral and intravenous administration of PRIMA-1.

PRIMA-1 induced apoptosis and slowed tumour growth in a mutant p53-dependent manner. TP53 mutants that are present in a number of different human cancers fail to bind the consensus DNA binding site, and Bykov et al. showed that treatment of cells with the compound restored DNA binding to 13 out of 14 TP53 mutants. PRIMA-1 also stimulated transcription of two classic p53 target genes — p21 and MDM2 — only in cells that express mutant forms of TP53.

Bykov et al. are not sure about the exact molecular mechanism of PRIMA-1. Studies with conformation-specific monoclonal antibodies revealed that the drug restores the wild-type structure to mutant p53. PRIMA-1 also rescued this conformation in the absence of other cellular proteins, indicating its ability to directly interact with p53. The authors are planning nuclear magnetic resonance and X-ray crystallography studies to further address questions about how the compound works. Other peptides and small molecules have been previously reported to protect p53 against denaturation or restore DNA binding activity to a mutant p53 domain. PRIMA-1 is the first molecule shown to convert p53 back into a properly folded, biologically active form.