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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.

Discovery of a chemical probe targeting the PWWP ___domain of NSD2 reveals insight into mechanisms that govern NSD2 localization. The compound and its negative control represent valuable tools for further defining NSD2 biology.

Arrowsmith and Schapira review recent progress in the discovery of drug-like small molecules that antagonize the function of non-bromodomain chromatin readers.

Selective inhibitors of protein methyltransferases are anticancer drug candidates. Yu et al. report the structural changes that occur when selective inhibitors bind to the protein methyltransferase DOT1L.

Owens et al. reported PFI-7, a selective and potent antagonist of GID4 of the CTLH E3 ligase complex, which enables identification of human GID4 targets. This study provides valuable insights into GID4 functions and a powerful tool for advancing new targeted protein degradation strategies.

Artificial intelligence is greatly accelerating research in drug discovery, but its development is still hindered by the lack of available data. Here the authors present data management and data science recommendations to help reach AI’s potential in the field.

PRDM9 is a PR ___domain containing histone methyl transferase which expression is normally restricted to the germline that has also been linked to a number of somatic cancers. Here the authors describe the identification of a small molecule that selectivity inhibits the methyltransferase activity of PRDM9 in biochemical and cellular assays

The SARS-CoV-2 NSP13 helicase is essential for viral replication and of interest as a drug target. Here, the authors present the crystal structures of NSP13 in the apo form and bound to either phosphate or the non-hydrolysable ATP analog AMP-PNP and discuss the helicase mechanism. They also perform a crystallographic fragment screening and identify 65 bound fragments, which could help in the design of new antiviral agents.

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.

Protein methyltransferases (PMTs) are epigenetic regulatory enzymes with significant therapeutic relevance. Here the authors describe a collection of chemical inhibitors and antagonists to modulate most of the key methylation marks on histones H3 and H4, and use the collection to study of the role of PMTs in mouse and human T cell differentiation.

Guido Sauter, Roland Eils, Christoph Plass, Raffaella Santoro and colleagues report that the gene encoding the epigenetic regulator BAZ2A is overexpressed in prostate cancer, where it interacts with EZH2 to induce aberrant gene silencing and cell proliferation. The authors find that BAZ2A levels are predictive of disease recurrence in patients with prostate cancer.

The p30 isoform of C/EBPα associated with leukemia interacts with WDR5, a component of the SET/MLL histone methyltransferase complex. A small molecule, OICR-9429, disrupted p30-WDR5 interactions, resulting in differentiation of p30-expressing leukemia cells.

Small molecules that induce targeted protein degradation by the ubiquitin–proteasome system, such as proteolysis-targeting chimeras (PROTACs), are attracting great interest as a new therapeutic modality. This Perspective discusses opportunities and challenges for expanding the applicability of targeted protein degradation, with a focus on the large family of E3 ubiquitin ligases that have a key role in the process.

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.

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.

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.

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.