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Despite recent setbacks with p53-activating small molecules including the nutlins, the cancer target keeps drug hunters coming back for more. Could immuno-oncology combinations, stapled peptides and targeted degraders unleash the therapeutic potential of the ‘guardian of the genome’?
When Lyubomir Vassilev, then a scientist at Roche, started in 2003 to write up his team’s discovery of small-molecule inhibitors of the p53–MDM2 interaction, he knew the paper would be big. p53 is the most frequently mutated gene in human cancer, after all, and his group had found tool compounds that could selectively boost the activity of the tumour suppressor. Disregarding the convention of naming new chemical matter with impenetrable company codes, he instead dubbed these compounds nutlins, after the facility in Nutley, New Jersey, where they were discovered.