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Chemical warfare agents (CWAs) are highly toxic compounds capable of causing mass casualties on the battlefield. Current analytical methods for detecting blister, nerve, and blood agents suffer from several inherent limitations, including false-positive results, high costs, susceptibility to environmental interferences and cross-contamination, and relatively cumbersome sample pretreatment and operational procedures. In this work, the authors report the design and synthesis of TrioAlert, a fluorescent sensor capable of simultaneously detecting the blister agent sulfur mustard, the G-type nerve agent sarin, and the blood agent cyanide within 90 s.

Mitochondrial cristae structure is essential for energy production and immune regulation, but therapeutic strategies targeting cristae remodeling are lacking. Here, the authors show that targeting triose phosphate isomerase 1 restores cristae architecture, rewires microglial metabolism, and protects against ischemic stroke.

Protein synthesis is tightly regulated by the integrated stress response, but therapeutic activation remains challenging. Here, the authors identify a drug‑like allosteric inhibitor, an ISRAC, that stabilises inactive eIF2B, mimicking stress‑induced eIF2α phosphorylation to activate the ISR, establishing eIF2B as a tractable target for ISR modulation.

Authors show that fat-pad biopsies from living ATTR-CM patients yield TTR fibril structures matching cardiac tissue. Cryo-EM reveals Congo Red and ThS bind a surface arginine site, informing tracer design for earlier, more accurate diagnoses.

Homologous recombination (HR) safeguards genome stability, but the regulation of HR proteins remains unclear. Here, the authors show that the compound UNI418 inhibits lipid kinases PIKfyve and PIP5K1C, reducing IP6 levels and triggering Cul4A–WDR5 dependent degradation of HR proteins, thereby suppressing HR and overcoming PARP inhibitor resistance.

Artificial intelligence is transforming drug discovery by enabling the generation of novel molecules with tailored properties, however, most generative efforts focus on physicochemical features or target binding, leaving phenotypic discovery largely unexplored. Here, the authors introduce an integrated framework combining high-throughput cytotoxicity screening with bioactivity signature-based machine learning predictors and reinforcement learning-driven generative models to create small molecules with selective cytotoxic activity in pancreatic cancer cells.

MYST acetyltransferases are an emerging class of therapeutic targets in cancer. Here, the authors report the dose-dependent inhibition of MYST enzymes by clinical inhibitors and define biomarkers to monitor selective target engagement.

The potency of a class of RAF kinase inhibitors was found to depend on cancer cell signaling activity. This insight informed reengineering of a clinically approved MEK inhibitor to block this cancer-driving pathway more effectively in combination.

DNA G-quadruplex (G4) structures can form at regulatory regions of transcriptionally active genes in open chromatin and are abundant in cancer states, but targeting G4-binding proteins in their native chromatin environment is challenging. Now bifunctional molecules that bind naturally occurring G4 sites and recruit ubiquitination machinery facilitate the degradation of G4-specific transcription factors and chromatin remodellers.

A chemoproteomic strategy reveals how posttranslational modifications reshape protein ligandability across the human proteome, uncovering more than 400 state-dependent interactions, including phosphorylation-driven control of KRAS inhibitor activity.

Crop losses from pests threaten global food security. Here, the authors survey the biosynthetic repertoire of hypocrealean fungi, identifying over 5,200 biosynthetic gene clusters, most encoding unknown products, and linking several to bioactive molecules for sustainable pest control.

N-desethyl-fluornitrazene is a µ-opioid receptor agonist derived from nitazenes that has supramaximal intrinsic efficacy that produces analgesia with minimal adverse effects in rodent models.

A small molecule, CLEO4-88, was identified that acts as a molecular glue, linking the E3 ligase subunit GID4 with ACAA1. Instead of triggering ACAA1 degradation, the compound inhibits its enzymatic activity.

The study reveals a ‘chemocentric’ strategy for identifying charged molecular glue degraders, through discovering a bromodomain-binding molecular glue degrader prodrug that is metabolically activated in cells to recruit the YPEL5-CTLH E3 ligase.

This study elucidates the structural mechanism of HEP-50768, a novel MRGPRX4 inverse agonist, and demonstrates its potent anti-itch efficacy and favorable safety in preclinical models, positioning it as a promising therapeutic for chronic pruritus.

A palladium-catalysed reaction converts hydrocarbon-derived precursors to chiral boron-containing nortricyclanes, and the shape of these nortricyclanes makes them plausible isosteres for meta disubstituted aromatic rings.

The dysregulation of the inositol-requiring enzyme 1 alpha (IRE1α) has been associated with multiple human diseases, so IRE1α-targeting small molecules present great therapeutic potential. Here, the authors report a series of substituted indoles as IRE1α inhibitors of good potency and selectivity, and show that the inhibitor IA107 allosterically inhibits IRE1α RNase activity via binding to the IRE1α kinase domain but without inhibiting the IRE1α dimerization.

Metronidazole targets stress responses in Helicobacter pylori, and ether analogues showed enhanced antibacterial potency and favourable pharmacology and achieved bacterial eradication in a mouse model.

Drug resistance and limited antifungal therapies necessitate innovative strategies. Using cis-fumaramidmycin-derived probes, the authors reveal inhibition of the Mrt4- rRNA interaction as a promising vulnerability for combating drug resistant fungi.

Direct reprogramming (DR) bypasses induced pluripotent stem cells to convert somatic cells directly into target cells, but identifying effective small molecules for DR remains challenging. Here, the authors introduce SuperDIRECTEUR, a computational method using single-cell temporal transcriptome data to predict small molecules for DR, demonstrating its potential in regenerative medicine by identifying stage-specific molecules for neuronal differentiation.

The cyclic five-membered disulfide 1,2-dithiolane holds promise as a recognition unit in probe design and drug development, but potential limitations in activation specificity, such as the diminished selectivity toward thioredoxin reductase (TrxR), raise concerns about its reliability in biological settings. Here, the authors systematically evaluate the activation behaviour of 1,2-dithiolane by synthesizing a panel of prodrugs and fluorescent probes incorporating either amine- or hydroxyl-linked cargoes, and show that TrxR-mediated selective activation of the 1,2-dithiolane unit is achievable when the cargo is incorporated within an amine-based framework.

Rheumatoid arthritis is a chronic inflammatory joint disease of autoimmune nature. This PrimeView focuses on the pathophysiology of the cartilage damage and bone erosion — the cardinal signs of rheumatoid arthritis.

Molecular glue degraders have consistently been discovered retrospectively, despite their increasing importance. Herein, a high-throughput approach is described that modifies existing ligands into molecular glue degraders.

The authors demonstrate that targeted protein degradation of the dengue virus capsid suppresses infection through capsid-dependent pathways rather than classical inhibition, revealing a new antiviral strategy effective against resistant viral variants.

Reactive oxygen species (ROS) serve as endogenous triggers for prodrugs, probes and materials, however ROS-activated bioorthogonal ligation remains as a challenge. Here, the authors report a ROS-activated tetrazine ligation enabled by boronate-caged dihydrotetrazines, and employ it for targeted protein degradation and tumor-selective drug delivery.

Kinases represent one of the largest superfamilies of drug targets, but many members have remained notoriously challenging to drug by traditional small-molecule approaches. This Review assesses approaches and agents aimed at therapeutically modulating kinases, comparing orthosteric, allosteric and induced-proximity strategies. Key obstacles and future directions are considered.

KRAS is an oncogene that switches between a GDP-bound inactive state and a GTP-bound active state. Recently developed KRAS G12C inhibitors are specific to the GDP-bound inactive state. Here, the authors develop a class of covalent KRAS G12C inhibitors capable of targeting both states for the treatment of KRAS-driven cancer.

An allosteric site on the E3 ligase adapter cereblon can be targeted to modulate the efficacy of cereblon in targeted protein degradation applications.

Thymine DNA glycosylase (TDG) was identified as a synthetic-lethal target in p53-deficient cancers through alterations in double-stranded RNA accumulation. A covalent small-molecule inhibitor of TDG exhibited potent efficacy against p53-deficient tumors.

Aryl sulfonamides and sultams are important pharmacophores in medicinal chemistry. Here, the authors report a practical palladium-catalyzed C–H activation assisted by amino-acid residues in the substrate leading to arylsulfonamides and bioactive peptidosulfonamide macrocycles.

Advanced NMR studies of catabolite activator protein show that allosteric inhibitors can prevent conformational changes needed for a protein to bind its ligand, offering an explanation for why these inhibitors may not appear to cause any effect when monitored using static techniques.

A structure-specific antibody generated and employed to visualize DNA G-quadruplex structures in human cells shows that these structures are modulated during the cell cycle and can be stabilized by a small-molecule ligand. This provides substantive evidence for endogenous DNA G-quadruplex formation in mammalian cells.

Precise genome editing in human pluripotent stem cells requires the development of methods for rapid and efficient genetic manipulation. Here, the authors screen for small molecules that enhance CRISPR-Cpf1-mediated genome engineering.

Polymerization-inducing chimeras are a novel bifunctional modality that uses protein symmetry to sequester targets by forming insoluble supramolecular assemblies. This approach overcomes reliance on accessory proteins and differs functionally from conventional inhibitors.

In this work authors demonstrate how photocontrolled tag-targeted degradation enables precise, spatiotemporal control of protein expression in tumor cells and CAR T cells, offering an esapproach for regulating engineered proteins with light.

EGFR inhibitors are standard of care in patients with EGFR-mutant non-small cell lung cancer (NSCLC) but resistance often develops. Here the authors report that the evolution of EGFR inhibitor resistance in EGFR-mutant NSCLC results in a sensitivity to the compound, MCB-613, and investigate the underlying mechanism of action.

Auvray and colleagues present a covalent fluorescent probe targeting tubulin, a key cytoskeletal protein. The probe is cell-permeable, fluorogenic, and STED-compatible, enabling clear, minimally-invasive imaging of dynamic processes in live and fixed cells.

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 findings reveal splicing modulator chemotypes and approaches to disrupt O-GlcNAc homeostasis.

Activity-based protein profiling identifies covalent small molecules that potentiate the activity of the METTL5:TRMT112 complex through binding to a complexoform-restricted allosteric pocket absent in other TRMT112:methyltransferase complexes

Photodynamic therapy is more effective if the photocatalyst works in hypoxic conditions. This protocol describes ENBSe, a photoredox catalyst driving NADH oxidation and initiating cytochrome c reduction, establishing a method for cancer phototherapy.

The CorA-associated type III-B CRISPR–Cas system synthesizes S-adenosyl methionine (SAM)-AMP, triggering immune responses. Through structural characterization and biochemical validation, Duan and Jin et al. unveil unique mechanisms for SAM-AMP synthesis and degradation and provide insights into the molecular basis of type III CRISPR–Cas signaling.

LRBA deficiency is associated with autoimmune disease and CTLA4 loss; this study identifies LRBA as a negative regulator of antitumor immunity and introduces LC427 as a promising small-molecule inhibitor of the CTLA4-LRBA interaction for cancer immunotherapy.

DNA repair pathways shape CRISPR editing outcomes. Here, authors identified FDA approved drugs that can be repurposed as repair modulators or to induce synthetic lethality, and uncovered new roles for ESR2 and AOX1 in DNA repair, enhancing editing and offering potential therapeutic applications.

Although FZDs are promising drug targets, so far no small molecules targeting them were described. Here, the authors report the a FZD7 core-targeting small molecule negative allosteric modulators of WNT-induced signaling, confirmed by pharmacology, structure determination and MD simulations.

Exploiting the high abundance of mutant p53 protein, a small molecule was developed that specifically binds to p53-Y220C mutants and delivers a mitosis blocker, killing TP53-mutant cancer cells while sparing healthy ones.

Bond et al. predict mechanism of action of hit compounds from a pooled screen of Mycobacterium tuberculosis mutants underproducing essential proteins by comparing the strain-specific responses of screening hits to those elicited by known antimicrobials.

Hydrogen sulfide (H₂S) reversibly modifies low molecular weight and protein thiols to form persulfides (RSS⁻) and polysulfides (RS(S)nS⁻) for antioxidant defence and regulation of activity. Here, the authors report a sensitive LC-MS/MS procedure that separately traps and quantifies the sulfur atom of H₂S, the terminal sulfur atom of RSS and RS(S)nS-, and the internal sulfur atoms of RS(S)nS ⁻ as diagnostic products in biological samples.