Fortifying p53 – beyond Mdm2 inhibitors

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.