Fortifying p53 – beyond Mdm2 inhibitors

Abstract

The tumor suppressor p53 is mutated in roughly 50% of all human malignancies. However, in the other 50% of tumors which retain wildtype p53, it appears insufficiently active to confer tumor suppression, through cell cycle arrest or apoptosis. Much of this p53-inactivation occurs through the Mdm2 oncoprotein, the product of a p53-inducible gene. Mdm2 is an E3 ubiquitin-ligase that targets p53 for proteasomal degradation. In 2004, a small-molecule antagonist of Mdm2 was identified, known as Nutlin-3a or Nutlin. It binds to Mdm2 at the p53 binding pocket, thereby leading to activation of p53 and its target genes [2]. Recently, similar Mdm2 antagonists were taken to clinical trials, such as RG7388 ({type:clinical-trial,attrs:{text:NCT02633059,term_id:NCT02633059}}NCT02633059, {type:clinical-trial,attrs:{text:NCT02407080,term_id:NCT02407080}}NCT02407080, {type:clinical-trial,attrs:{text:NCT02828930,term_id:NCT02828930}}NCT02828930, {type:clinical-trial,attrs:{text:NCT02670044,term_id:NCT02670044}}NCT02670044, {type:clinical-trial,attrs:{text:NCT02545283,term_id:NCT02545283}}NCT02545283, {type:clinical-trial,attrs:{text:NCT02624986,term_id:NCT02624986}}NCT02624986), HDM201 ({type:clinical-trial,attrs:{text:NCT02780128,term_id:NCT02780128}}NCT02780128, {type:clinical-trial,attrs:{text:NCT02143635,term_id:NCT02143635}}NCT02143635), and MI-773 ({type:clinical-trial,attrs:{text:NCT01636479,term_id:NCT01636479}}NCT01636479), but the results regarding their efficacy have not been reported so far. Thus, delivering a wake-up call to dormant p53 in tumors remains a tempting but currently not proven option for cancer therapy.