Volume 19 Issue 8, August 2020

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’?

Several biological phenomena alter the ageing process. This Review discusses the most promising agents to slow ageing, separating them into two tiers based on their efficacy and evidence. The potential use of some interventions in clinical trials to expand overall healthspan as well as how those interventions could be assessed are also discussed.

RAS proteins, which are frequently altered in cancer, were once considered undruggable, but compounds targeting some mutant RAS proteins have recently demonstrated clinical efficacy. In this Review, Malek and colleagues explore how these and other drugs that target RAS or associated pathways might be used effectively, particularly in combinations, and discuss other RAS-targeted therapies in the pipeline.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) — a key mediator of cell death and inflammation — is activated in human diseases. Here, Yuan and colleagues discuss current understanding of RIPK1 biology and its association with diseases including inflammatory and autoimmune disorders, neurodegenerative diseases and sepsis. The clinical development of small-molecule RIPK1 inhibitors and associated challenges are discussed.