Nature Reviews Molecular Cell Biology, Published online: 19 February 2026; doi:10.1038/s41580-026-00955-3In this Tools of the Trade article, Alison Mody (Woo lab) discusses a proximity-induced platform for targeted O-GlcNAcylation of proteins of interest, enabling researchers to measure the effect of O-GlcNAcylation on protein function.

Authors report drug repurposing screens against O-GlcNAc cycling enzymes, finding kinase inhibitors that act as splicing modulators to disrupt O-GlcNAc homeostasis and downregulate OGT and OGA. These ...

Diet can impact anticancer drug activity. A classic example in rodents is a ketogenic diet enhancing PI3K inhibitor activity. Here, we show that phytochemicals and their microbiome derivatives, rather...

Base editors can correct disease-causing genetic variants. After a neonate had received a diagnosis of severe carbamoyl-phosphate synthetase 1 deficiency, a disease with an estimated 50% mortality ...

Uechi et al. found that a small-molecule lipoamide dissolves stress granules (SGs) by targeting SFPQ, a redox-sensitive disordered SG protein, alleviating pathological phenotypes caused by amyotrophic...

Competitive (nondegradative) molecular glues represent a promising drug modality that remains underexplored primarily due to the lack of adequate hit identification approaches. In this study, we screened our historically grown FKBP-focused library containing >1000 drug-like molecules to identify FKBP-assisted molecular glues targeting a diverse panel of 57 proteins. In addition to establishing a robust and generalizable screening approach, we discovered three novel FKBP-dependent molecular glues targeting PTPRN, BRD4BD2, and STAT4. Our results demonstrate that molecular glues are more common than previously thought and that they can be identified by repurposing existing focused libraries. An optimized, highly cooperative FKBP12-BRD4BD2 glue demonstrated the involvement of the BD2 pocket and exhibited selectivity over the closely related BD1 domain. Our results underscore the value of FKBP12-assisted molecular glues to target challenging proteins with the potential for high selectivity.

Targeted protein degradation (TPD) is an emerging therapeutic modality in which small molecules are used to recruit targets to the natural protein degradation machinery of the cell. Molecular glue deg...

The BRCC36 isopeptidase complex (BRISC) is a deubiquitylase that stabilizes interferon receptors, driving inflammation. We discovered ‘BRISC molecular glue’ inhibitors (BLUEs) that selectively inactiv...

Molecules that can perturb protein-protein interactions have an immense impact on chemical biology and therapeutics. However, such compounds typically rely on accessory proteins to function, such as E...

Vitamin C directly modifies lysine residues through vitcylation, regulating STAT1 signaling and enhancing anti-tumor immune responses by preventing STAT1 dephosphorylation.

Phagocytosed bacteria can serve as an alternative nutrient source for macrophages, influencing their metabolic and immune responses through the recycling of microbial components, with the process regu...

Small molecules that induce non-apoptotic cell death are of fundamental mechanistic interest and may be useful to treat certain cancers. Here, we report that tegavivint, a drug candidate undergoing hu...

Fifteen years ago, an analysis of drug molecules moving through the stages of clinical development suggested that increased three-dimensional character was a marker of greater success. Now, we perform...

Misregulation of protein–protein interactions (PPIs) underlies many diseases; hence, molecules that stabilize PPIs, known as molecular glues, are promising drug candidates. Identification of novel mol...

Vertex Pharmaceuticals won FDA approval for a non-opioid drug for moderate to severe acute pain

SCF–FBXO31 scans proteins for C-terminal amidation and marks them for subsequent proteasomal degradation.

Dimethyl fumarate (DMF) is an established oral therapy for multiple sclerosis worldwide. Although the clinical efficacy of these fumarate esters has been extensively investigated, the mode of action and pharmacokinetics of fumarates have not been fully elucidated due to their broad-spectrum reactivity and complex metabolism in vivo. To better understand the mechanism of action of DMF and its active metabolite, monomethyl fumarate (MMF), we designed and utilized clickable probes to visualize and enrich probe-modified proteins. We further perform quantitative chemoproteomics analysis for proteome-wide target identification and validate several unique and shared targets of DMF and MMF, which provide insight into the reactivity, selectivity, and target engagement of fumarates.

Circulating proteins are common targets for the discovery of occupancy-based inhibitors including monoclonal antibodies. Effective inhibition of target pathogenicity with blocking approaches, however,...

Small-molecule ligands have been developed that covalently attach to their cognate RNA aptamers in vitro and in living cells. This strategy opens up new avenues for RNA imaging applications (for examp...

Shen and Yin developed a technology named FUSEP to profile the E2-specific ubiquitome that makes use of a fusion between E2 and ubiquitin carrying a R74G point mutation, which leaves an LGGG remnant f...

Small molecule degraders such as PROteolysis TArgeting Chimeras (PROTACs) and molecular glues are new modalities for drug development and important tools for target validation. When appropriately opti...

Transcription inhibitors also disrupt nuclear export. Here, Williams et al. reveal that mRNA export factors sense transcription inhibition and adapt by storing mature export-competent mRNA in nuclear speckles. This enables rapid release when transcription resumes and ensures retention of cellular identity and viability during a transient global transcription insult.

Tan et al. designed a DNA-encoded library, comprising compact and diverse linkers, that recruits FKBP12 to any protein of interest to enable efficient discovery of non-degrader proximity inducers. The screen uncovered a compound that stabilized and reversed functional defects of the ATG16L1 T300A IBD risk variant in an FKBP12-independent manner.

Organelle proteomics defines the cellular landscape of protein localization and highlights the role of subcellular remodeling in driving responses to perturbations such as viral infections.

Former President Jimmy Carter, who died Sunday at age 100, gave visibility to devastating health problems that are often invisible.

Trussina et al. demonstrate that the storage of mRNA molecules inside G3BP1-driven RNP granules facilitates the formation of RNA-RNA interactions, preventing the mRNA from being translated. The DEAD-box helicase DDX3X facilitates RNP granule dissolution by attenuating these inhibitory RNA-RNA interactions to aid restart of mRNA translation.

Cellular activity is spatially organized across different organelles. While several structures are well-characterized, many organelles have unknown roles. Profiling biomolecular composition is key to ...

Molecules that are able to induce proximity between two proteins are finding ever increasing applications in chemical biology and drug discovery. The ability to introduce an electrophile and make such proximity inducers covalent can offer improved properties such as selectivity, potency, duration of action, and reduced molecular size. This concept has been heavily explored in the context of targeted degradation in particular for bivalent molecules, but recently, additional applications are reported in other contexts, as well as for monovalent molecular glues. This is a comprehensive review of reported covalent proximity inducers, aiming to identify common trends and current gaps in their discovery and application.

Palleon Pharmaceuticals, a company pioneering glyco-immunology drug development to treat autoimmune diseases and cancer, today announced a collaborati

The U.S. has confirmed its first known severe human infection of H5N1 bird flu, in a person in Louisiana.