Awakening guardian angels: drugging the p53 pathway

Abstract

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.

Discovery of Potent and Orally Active p53-MDM2 Inhibitors RO5353 and RO2468 for Potential Clinical Development

“…6−8 In tumor cells with wild-type p53 (∼50%), reactivation of the p53 pathway by inhibition of MDM2 with small molecules has been considered as potentially an attractive novel therapeutic approach for cancer treatment. 9,10 Currently, several smallmolecule MDM2 inhibitors including RG7112 and RG7388 ( Figure 1) are undergoing clinical evaluations. 11−14 To maximize the chance of success in the clinic and derisk any potential idiopathic toxicity associated with specific chemotypes, continued research efforts are required to expand chemodiversity and identify potent and selective MDM2 antagonists with desirable in vitro ADMET and in vivo pharmacokinetic properties.…”

Stabilization of protein–protein interactions by small molecules

“…Whereas inhibition of binding of MDM2 to p53 has successfully been achieved by several small molecules [85], no such specific molecules have been reported for MDMX. However, to take full advantage of the strategy to stabilize p53 function, MDM2 and MDMX need to be targeted [86].…”

Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

“…Those studies suggested that the reactivation of the p53 pathway in tumors has the potential to reduce tumor growth either in combination with other therapies or alone. Therefore, there is a growing interest in understanding the mechanisms of p53 inactivation and the therapeutic possibilities of reactivating dysfunctional p53 in cancers in order to halt tumor growth (Brown et al, 2009). In this review, we will focus on the role of homeodomain-interacting protein kinase-2 (HIPK2) in p53 activation.…”