Volume 20 Issue 10, October 2021

AlphaFold and RoseTTAFold have delivered a revolutionary advance for protein structure predictions, but the implications for drug discovery are more incremental. For now.

PI3K signalling is one of the most frequently aberrantly activated pathways in cancer. However, the development of therapeutic PI3K pathway inhibitors has faced challenges including poor drug tolerance and drug resistance. Here, Vanhaesebroeck et al. review efforts to understand and therapeutically exploit the biology of PI3Kα and PI3Kδ — the key targets of currently approved PI3K inhibitors, highlighting lessons learned and future opportunities.

Numerous kidney diseases are characterized by a breakdown of the glomerular filtration barrier, which forms the interface between the blood and urine. In this Review, Daehn and Duffield discuss strategies to target components of this barrier, focusing on mechanisms to control mitochondrial function and the actin–myosin machinery, to improve kidney function in individuals with kidney diseases.

Targeted protein degradation by proteolysis-targeting chimeras (PROTACs) is attracting substantial interest as a therapeutic modality that could circumvent some limitations of traditional small-molecule drugs. This article presents a systematic approach to assessing the PROTAC tractability (PROTACtability) of protein targets, which could support decision-making on whether a particular target may be amenable to modulation using a PROTAC.