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Eukaryotic elongation factor 1 alpha (eEF1A) is subject to extensive post-translational methylation but not all responsible enzymes are known. Here, the authors identify METTL13 as an eEF1A methyltransferase with dual specificity, which is involved in the codon-specific modulation of mRNA translation.

Computer vision coupled with gene expression shed light on the collective organizational patterning of glioma stem cells, which correlates with glioma stem cell phenotypes

A substantial obstacle in basic research is the use of poorly validated tool compounds with purported useful biological functions. Here, the authors systematically profile widely used histone acetyltransferase inhibitors and find that the majority are nonselective interference compounds.

A pyrrolidine-based small-molecule inhibitor competes with H3K27me3 for binding to EED leading to inactivation of PRC2 and global reduction in H3K27me3 levels.

Adoptive T cell therapy using an allogeneic T cell graft is an encouraging therapeutic approach in cancer, but issues such as graft-versus-host disease can hinder applicability. Here, the authors show that DOT1L inhibition or DUSP6 overexpression in T cells attenuates graft-versus-host disease but retains anti-tumour activity in mouse models.

Chromodomains in chromatin-associated proteins act as ‘readers’ of methylated lysines within histones. Structural and computational design led to the identification of UNC3866, a potent, cell-active peptide-based inhibitor of the methyllysine reading functions of CBX and CDY chromodomains.

The histone methyltransferase DOT1L and the chromatin reader BRD4 together facilitate transcription of genes critical to the molecular pathogenesis of MLL leukemia.

Mammalian RPRD proteins bind the phosphorylated CTD of RNA pol II with different affinities. Structural elucidation and characterization of their CTD interaction domains reveal the basis of RPRD binding preferences and a role in directing CTD dephosphorylation.

The presence of bivalent epigenetic active and repressive histone marks control lineage-specific differentiation in embryonic stem cells. Here, the authors reveal that bivalent marks repress the differentiation gene IHH in colorectal cancer-initiating cells, and can be targeted by EZH2 inhibition

Cancer stem cells are thought to be resistant to anticancer therapies and are able to repopulate tumors and sustain tumor growth. The authors establish BMI-1 as a crucial regulator of cancer cell stemness in colorectal tumors and develop a chemical inhibitor that targets cancer stem cell renewal by reducing the levels of BMI-1. This strategy affords antitumor effects in vitro and in vivo and may pave the way for the precise targeting of elusive cancer stem cells.

AlphaFold is a breakthrough in protein structure prediction, but limitations in its application to computation- and structure-guided drug discovery remain. As with structure prediction, public-domain data and benchmarking initiatives will be essential to advance the field of computational drug design.

Harding et al. present a biophysical and structural characterization of the complex between huntingtin (HTT) and HAP40 proteins. They show that the abundance of HAP40 is coupled with that of HTT and that there is greater conformational variety in the exon 1 of the mutant HTT than WT, important for the future drug discovery studies targeting Huntington’s disease.

The Structural Genomics Consortium (SGC) and its clinical, industry and disease-foundation partners are launching open-source preclinical translational medicine studies.

OICR-41103 is a potent, selective probe targeting the DCAF1 WDR domain and displacing viral Vpr protein. It enables new opportunities in cancer research, antiviral therapy, and targeted protein degradation via PROTACs.

WD40 repeat (WDR) domain-containing proteins are involved in numerous protein complexes that have been linked to disease. Schapira and colleagues describe recent advances in targeting WDR domains with small molecules to potently inhibit protein–protein interactions, and discuss the potential for the diversity and druggability of WDR domains to open up new pathways for therapeutic intervention.

The reproducibility of biomedical research on novel drug targets has become suspect. Here, we highlight how drug discovery centres embedded in academic institutions, but with a translational imperative, can help address this reproducibility crisis.

Epigenetic chemical probes are having a strong impact in biological discovery and target validation. Systematic coverage of emerging epigenetic target classes with these potent, selective, cell-active chemical tools will profoundly influence understanding of the human biology and pathology of chromatin-templated mechanisms.

Epigenetic regulation of gene expression can contribute to diseases such as cancer, inflammation and neuropsychiatric disorders. Here, the authors review the protein families that mediate epigenetic signalling through histone acetylation and methylation, and highlight progress in the pharmacological modulation of each class of proteins.

Human pluripotent stem cells can be differentiated into exocrine pancreas progenitor organoids, allowing studies of development and pancreatic cancer modeling.

A quantitative mass spectrometry–based standard operating procedure to classify antibody performance in immunoprecipitation is assessed in a multilaboratory study.

WDR26 and muskelin mediate the formation of two distinct CTLH E3 ligase complexes that have different targets. Inhibition of mTOR signalling regulates muskelin-specific CTLH complex activity in human cells and leads to muskelin autoregulation.

Six WWE domain-containing proteins also contain domains with E3 ubiquitin ligase activity. We report structures, biophysical and biochemical assays for the discovery of novel WWE domain binders and their respective application.

Critical Assessment of Computational Hit-finding Experiments (CACHE) is a public benchmarking project to compare and improve computational small-molecule hit-finding approaches through cycles of prediction, compound synthesis and experimental testing. By that, CACHE will enable a more efficient and effective approach to hit identification and drug discovery.

This Perspective highlights the importance of protein–protein interactions for the oncogenic functions of MYC and discusses how the MYC protein interactome might be exploited therapeutically.

Structural and biophysical characterization of a small molecule binding to Cbl-b E3 ligase reveals an intramolecular glue mechanism locking the protein in an inactive state.

Target 2035 aims to develop a potent and selective pharmacological modulator for every human protein by 2035 with the results made publicly available. This Roadmap article sets out how that will be achieved.

Protein arginine methyltransferases (PRMTs) regulate numerous biological processes, including transcription, splicing and the DNA damage response. In this article, Barsyte-Lovejoy and colleagues discuss the development of PRMT inhibitors, predominantly for cancer, and describe the challenges and potential new indications in which PRMT inhibition could be therapeutically relevant.

Chemical probes are powerful reagents with increasing impacts on biomedical research. However, probes of poor quality or that are used incorrectly generate misleading results. To help address these shortcomings, we will create a community-driven wiki resource to improve quality and convey current best practice.

A multilaboratory pilot project demonstrates that hybridoma and phage display technologies can be applied to produce high-affinity, high-specificity renewable antibodies to a set of 20 human SH2 domain proteins in a reasonable time frame, suggesting that a systematic, large-scale effort to generate renewable protein binders will be feasible.