Upstream targets in the p53 pathway

Abstract

Small molecule reactivation of mutant forms of the tumour suppressor p53 or wild-type p53 function is an accepted strategy for the development of anticancer therapies. Both mutant and wild-type protein can be reactivated via direct binding of small molecules, but it is also possible to achieve this by targeting proteins involved in the regulation of p53. As many tumours contain wild-type p53 protein that is rendered inactive via disruption of its upstream regulatory pathways, the identification of small molecules that enhance wild-type p53 activity through targeting its regulators has become important in the search for novel anticancer drugs. Here we summarise recent developments in the search for these kinds of small molecules. Amongst the processes targeted by these compounds are p53 ubiquitination/degradation, acetylation/deacetylation, nuclear transport and ribonucleotide synthesis. DNA intercalating compounds that cause little damage to DNA and mitotic poisons are also mentioned.