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Small molecules are low molecular weight molecules that include lipids, monosaccharides, second messengers, other natural products and metabolites, as well as drugs and other xenobiotics. They are distinct from macromolecules such as proteins. In chemical biology, this term also covers metal ions and in this discipline small molecules may play the role of a chemical tool.
The reliable design of small-molecule binders to target RNAs remains challenging. Recognizing hidden pockets that are transiently occupied by intramolecular nucleobase intercalation brings us closer to achieving this goal.
A novel state-of-the-art approach for absolute binding free energies of RNA-binding small molecules paves the way to the routine use of free-energy simulations in drug discovery targeting RNA systems, reducing failure rates.
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.
STING is a promising drug target, but selective activation is necessary for safety and efficacy. Researchers have developed a two-component prodrug system for potent pharmacological activation of STING that offers excellent tumour targeting.
The reliable design of small-molecule binders to target RNAs remains challenging. Recognizing hidden pockets that are transiently occupied by intramolecular nucleobase intercalation brings us closer to achieving this goal.
Cereblon-based molecular glue degraders provide a powerful strategy to target previously intractable proteins. This approach has now enabled selective elimination of a metabolically essential zinc finger transcription factor that drives resistance to KRAS inhibition in pancreatic cancer.
The discovery of lipoamide offers a unique approach to modulate stress granule dynamics. It will advance studies of stress granule biology and inform the therapeutic modification of these biomolecular condensates as a potential treatment option for amyotrophic lateral sclerosis.
Molecular glue degraders are small molecules that have major therapeutic potential. Here, protein microarrays enabled the identification of proteins that can be glued to the VHL E3 ligase and degraded with VHL targeting ligands.
