This Perspective discusses the application of algorithmic methods throughout the preclinical phases of drug discovery to accelerate initial hit discovery, mechanism-of-action elucidation and chemical property optimization.

RAS proteins, central drivers of cancer, appeared ‘undruggable’ for almost 30 years. Here we provide a personal perspective on the effort leading to our initial report of KRAS^G12C inhibitors in 2013, and the decade of discoveries that followed.

Boron is a common element found in various minerals; however, it is not used in life-creating machinery in nature. In a new study, boron enzymes have been created by introducing a boronic acid-containing non-canonical amino acid into an artificial enzyme scaffold. Further development via directed evolution enabled the selection of new-to-nature stereoselective chemistry.

The inaugural CRISPR-based drug Casgevy has been approved by several medical agencies, with other CRISPR-based therapies currently in clinical trials. Although there are technological hurdles to overcome, chemical biology has a vital role in developing recent breakthroughs in base editing, prime editing and epigenetic editing into future treatments.

Cryo-electron microscopy and biochemical analysis reveal the activation mechanism of protein arginine kinase McsB by its activator McsA for protein quality control under stress in Gram-positive bacteria.

Development of a ligand-based proximity labeling strategy enables interrogation of the native cell membrane interactome for the GLP-1 receptor in two cell types, revealing new regulators of receptor-mediated signaling and β cell responses.

Development of a biosensor for GPCR trafficking to the lysosome combined with a genome-wide CRISPR screen identified DNAJC13 as a critical regulator of agonist-induced trafficking of the δ-opioid receptor to the lysosome.

Qiao and Nguyen et al. describe a strategy to block hypoxia-dependent gene expression in cell and mouse models of breast cancer through dual targeting of X-box-binding protein 1 and hypoxia-inducible factor binding to DNA with fully synthetic, stabilized artificial transcription factors.

Cao et al. introduce artificial lncRNA (alncRNA) for targeted protein degradation by engineering and linking lncRNA HOTAIR sequence to RNA aptamers. The resulting alncRNAs degrade oncogenic proteins, such as c-MYC and KRAS, showing promise for cancer therapies.

Pan et al. establish a general photoproximity labeling approach in living cells, applying microenvironment mapping with a HaloTag-based platform (HaloMap) to profile the stress granule proteome and identify ubiquitin-related modulators as key mediators of granule disassembly.

Computational methods for calculating a protein structure from a given amino acid sequence have revolutionized both our understanding of structural biology and the prediction of protein-binding compounds. This issue features several pieces that explore machine learning approaches for protein structure prediction, benchmarking and evaluation of model quality, and how machine learning algorithms can be used in the drug discovery process.