Nutlin

We have all heard of p53, usually in a negative way. We know that cancer patients whose p53 has gone missing have bad news disease. It is the gene that is most commonly disrupted in cancer. In CLL deletion of 17p13, where the p53 gene is located, or mutation of the gene so as to make it non-functional, leads to poor prognosis, drug-resistant disease. So what does p53 do?

It is often called the Guardian of the Genome, meaning that it's role is to guard against copying errors in the DNA. The idea is that it recognizes when a mistake is made, puts the cell into stasis to see if it can be repaired, and if it can't, orders the cell to kill itself. It's a dangerous molecule to have around; kept on a leash doing what it's told it serves an essential function; let loose, like the dogs of war, it could cause untold damage.

One of the ways of controlling p53 is through the molecule MDM2 (it stands for Murine Double Minute - a reference to the mouse chromosome it is found on). In humans mdm2 is on the short arm of chromosome12. MDM2 is the master regulator of p53. (By the way, if you are getting confused by the use of italics, the covention is that the gene is in italics and small letters whereas the protein is not italicized and often capital letters are used. p stands for protein and the 53 refers to the molecular weight in kiloDaltons. there are other important molecules called p21 and p16 etc.)

MDM2 controls p53 in several ways, including blocking its transactivation domain so that it blocks its ability to activate transcription, also by aiding the nuclear export of p53 and by acting as a ubiquitin ligase to promote p53 degradation by proteosomes. Normally a cell has very low levels of both p53 and MDM2. It has been well demonstrated that disruption of p53-MDM2 interaction leads to activation of p53 and tumor suppression, but until recently disrupting this interaction has been very difficult. The breakthrough came from examining the crystal structure of MDM2 which showed that there is a relatively deep hydrophobic (= water repelling) pocket in the molecule which raised the possibility that small molecular weight molecules might be able to block the interaction with p53. Scientists at Roche have been screening molecules that might do this. They hit upon a series of molecules called cis-imidazolines (Chaya will understand precisely what this means) which they named Nutlins. The name puzzled me for a while until I realized that the Roche Research Institute is based at Nutley, New Jersey. Thus Nutley inhibitors.

The nutlins have been shown to activate the p53 pathway and to have anti-tumor effects in tumor cell lines, especially in those that over-express MDM2. and including some cell lines derived from acute myeloid leukemia and myeloma. In fresh CLL cells the nutlins activate the p53 pathway and induce apoptosis. They synergize with fludarabine and chlorambucil and they are much less toxic to noemal T cells.

They seem to have great promise in CLL; they are orally available and they penetrate cell membranes. Of course they have yet to be tried out in patients, but it can't be long before they are in clinical trials. In order to act they require an intact p53 pathway, so they will of no use in drug resistant CLL, but nevertheless to have a non-toxic agent in CLL that works will be a great boon.