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A phenotypic cell-based screen identifies an inhibitor of BET bromodomain transcriptional activity via inhibition of the alternative bromodomain-containing protein TAF1.
Biomolecule-specific small-molecule probes, in contrast to genetically encoded tags, can visualize peptidoglycan, lipids, nucleic acids and glycans and have proven useful for imaging of the unique subcellular compartments and environment of bacteria.
The glycolytic enzymes GAPDH and pyruvate kinase produce 4-phosphoerythronate and 2-phospho-L-lactate, which block metabolic flux. A newly identified conserved metabolic repair enzyme, phosphoglycolate phosphatase, eliminates these side products.
A small-molecule compound binds to the RGS domain of axin, promotes the degradation of β-catenin and Ras through the GSK3β-mediated destruction complex, and reduces the growth of KRAS and APC mutant colorectal cancer cell lines.
A newly synthesized nitroxide-based probe containing a fluorophore with high quantum yield at relatively long wavelengths can detect endogenously derived lipid-derived radicals and has therapeutic potential in a model of hepatocellular carcinoma.
A pH-activatable fluorescent sensor targeted to bone tissue allows intravital imaging of osteoclast pH changes with greater photo-stability in mice, revealing insights into osteoclast motility and proton extrusion.
Biochemical analysis, and imaging using a copper-sensitive fluorescent sensor, demonstrate that copper regulates cAMP-mediated lipolysis by inhibiting the activity of the cAMP-degrading phosphodiesterase PDE3B.
Small molecules identified in two high-throughput screens modulate a strobe-light-induced fear response in zebrafish larvae described as ‘innate freezing’. Some compounds cause escape-like behavior, including several that target the sigma-1 (σ1) receptor.
A screening approach involving ten larval zebrafish behavior assays and the similarity search tool, phenoBlast, for compounds that phenocopy the antipsychotic haloperidol identifies finazines that may work partially through the sigma-1 (σ1) receptor.
An siRNA screen of cells treated with a mitochondrial-targeted DNA oxidizing agent identifies proteins such as RAD23A, XRCC4, and POLθ that mediate mitochondrial DNA repair and replication.
KDM5 histone demethylases promote the survival of drug-tolerant persister (DTP) cells in certain cancers. CPI-455, a chemical probe specific for KDM5, elevates cellular H3K4 methylation levels and reduces DTP cell numbers, suggesting that KDM5 is a viable target for cancer combination treatment.
X-ray crystallographic analyses of KDM5B provide a view of the enzyme's iron(II)- and 2-oxoglutarate-containing catalytic core, and structures of KDM5B complexes with small-molecule inhibitors reveal selectivity profiles for multiple compound chemotypes.
Human mitochondrial tRNAMet has a 5-formylcytidine (f5C) modification at the first anticodon position that is required for correct decoding of the AUA codon as methionine. The first step in the biosynthesis of f5C involves the S-adenosylmethionine-dependent methylation of cytidine 34 by the NSUN3 methyltransferase.
A small molecule has been identified that can mitigate the progression of an inherited form of deafness in transgenic mice by stabilizing mutant clarin-1, an essential component of a multimolecular complex of the mechanotransduction apparatus of hair cells in the inner ear.
Phosphoglycerate dehydrogenase (PHGDH) is an enzyme of serine biosynthesis overexpressed in various types of cancer. A new series of PHGDH inhibitors selectively block proliferation of PHGDH-dependent cancer cells and reveal an unexpected role of serine biosynthesis in coordinating one-carbon metabolism.
