Target validation articles from across Nature Portfolio

NanoLuciferase- and HaloTag-based screening technologies are versatile tools suitable for the live-cell analysis of the entire small-molecule-induced degradation cascade to uncover the mode of action of proximity-inducing compounds such as PROTACs.

Human genetic evidence increases the success rate of drugs from clinical development to approval but we are still far from reaching peak genetic insights to aid the discovery of targets for more effective drugs.

Exportin-1 (XPO1) was identified as the target of small molecules suppressing T cell activation. Selective disruption of the chromatin scaffolding function of XPO1 without blocking nuclear export implicates XPO1 as a target in autoimmunity.

Wenzell et al. developed a massively parallel screening platform to interrogate the sensitivity of signal peptides (SPs) to Sec61 inhibitors. The platform revealed how distinct inhibitors achieve sequence-dependent SP discrimination.

The recent design of mutation-selective KRAS inhibitors has led to US Food and Drug Administration approval of two inhibitors of KRAS(G12C), sotorasib and adagrasib. A study published in Nature reports the development of a first-in-class pan-KRAS-selective inhibitor. Here we comment on the current status of KRAS-targeting approaches.

Two new studies exploring PROTAC-mediated degradation of SMARCA2 for cancer therapy solve an apparently intractable selectivity challenge with SMARCA4 by utilising the requirement for a productive ternary complex between the protein, PROTAC and ligase complex.

Protein structures predicted using artificial intelligence will aid medical research, but the greatest benefit will come if clinical data can be similarly used to better understand human disease.