Small molecules articles within Nature Chemical Biology

Featured

  • Article |

    The protein phosphatase LYP is known to regulate signaling in the immune system, but the regulatory mechanisms controlling LYP itself are less clear. Exploration of spatiotemporal dynamics and application of a newly identified chemical inhibitor now define a role for the kinase CSK in dialing down LYP activity.

    • Torkel Vang
    • , Wallace H Liu
    •  & Lutz Tautz

  • News & Views |

    The activity of the anaphase-promoting complex is regulated by the autoubiquitination of Cdc20. How this autoubiquitination is regulated remains an open question. The pharmacological inhibitor TAME now provides insight into this regulation.

    • Ian T Foe
    •  & David P Toczyski

  • News & Views |

    Inositol tetraphosphate is required for both the incorporation of the histone deacetylase HDAC3 into a repressive complex and its enzymatic activity.

    • Tatiana G Kutateladze

  • Article |

    Identifying DNA sequences that adopt alternative structures within the context of genomic DNA presents a major challenge. Pyridostatin, a G-quadruplex–specific chemical probe, was shown to induce DNA damage at specific genomic sites, including the proto-oncogene SRC, leading to cell cycle arrest in human cancer cells.

    • Raphaël Rodriguez
    • , Kyle M Miller
    •  & Stephen P Jackson

  • Article |

    MLL fusion genes often encode leukemogenic proteins that depend on interaction with menin, a component of the MLL SET1-like histone methyltransferase complex. MI-2 and MI-3 are the first small molecules that can block menin–MLL fusion protein interaction and their oncogenic effects in cells.

    • Jolanta Grembecka
    • , Shihan He
    •  & Tomasz Cierpicki

  • Article |

    20(S)-hydroxycholesterol binds to Smo at a site distinct from cyclopamine and activates signaling via an allosteric mechanism. A new alkyne oxysterol analog selectively captures Smo from membrane extracts and provides a new method for detecting protein-sterol interactions.

    • Sigrid Nachtergaele
    • , Laurel K Mydock
    •  & Rajat Rohatgi

  • Article |

    DNA repair proteins require efficient pathways to search for DNA damage lesions within a large genome. Kinetic trapping experiments define the rates of human uracil DNA glycosylase hopping and sliding along damaged DNA substrates and highlight the role of the phosphodiester backbone in DNA sliding.

    • Joseph D Schonhoft
    •  & James T Stivers

  • Article |

    Screens of large compound libraries identify new small–molecule proteostasis regulators that, by enhancing the activity of the heat shock response factor HSF–1 and by activating other components of the proteostasis network, such as the antioxidant response or the unfolded protein response pathways, restore protein folding in multiple models of protein conformational diseases.

    • Barbara Calamini
    • , Maria Catarina Silva
    •  & Richard I Morimoto

  • Article |

    Rapid reversible inhibitors of the oxygenation activity of COX-2, including ibuprofen and naproxen, selectively inhibit the enzyme with endocannabinoid 2-AG substrates but not with arachidonic acid, and this substrate-selective inhibition may be important for the analgesic activity of the drugs.

    • Kelsey C Duggan
    • , Daniel J Hermanson
    •  & Lawrence J Marnett

  • Article |

    Mono- and digalactosyldiacylglycerols (MGDGs and DGDGs) are glycolipids that are central to plant metabolism and photosynthetic membrane biogenesis. Galvestine-1, a small molecule inhibitor of MGDG synthases that was identified in a high-throughput chemical screen in Arabidopsis thaliana, reveals a new role for these galactolipids in pollen-tube development.

    • Cyrille Y Botté
    • , Michael Deligny
    •  & Eric Maréchal

  • Article |

    The inhibitor PU-H71 preferentially targets tumor-enriched Hsp90 complexes. Affinity purification using PU-H71 reveals cancer-specific protein networks in chronic myeloid leukemia and that the abundance of tumor-specific Hsp90 clients in cells can predict sensitivity to Hsp90 inhibitors.

    • Kamalika Moulick
    • , James H Ahn
    •  & Gabriela Chiosis

  • Article |

    A screen for compounds that alleviate the inhibitory effect of influenza NS1 on host gene expression and suppress viral toxicity found naphthalimides that could upregulate REDD1, an mTORC1 inhibitor, revealing that viruses inhibit REDD1 to activate the mTORC1 pathway.

    • Miguel A Mata
    • , Neal Satterly
    •  & Beatriz M A Fontoura

  • Article |

    The synthetic compound Shield-1 can already be used to protect designed fusion proteins from degradation. The development of a new protein domain that is degraded upon addition of Shield-1 expands the compound's utility in controlling protein function and allows the simultaneous degradation and stabilization of different constructs.

    • Kimberly M Bonger
    • , Ling-chun Chen
    •  & Thomas J Wandless

  • Article |

    A search through hydrophobic chemical space identifies an adamantane tag that targets dehalogenase fusion proteins for degradation, as demonstrated for both cytosolic and transmembrane proteins; and in zebrafish and mice. This molecule provides a new tool to study protein function with precise control.

    • Taavi K Neklesa
    • , Hyun Seop Tae
    •  & Craig M Crews

  • Article |

    Protein-focused lead-identification strategies may be limited in their ability to identify small molecules that bind to cellular RNAs. Docking small molecules against the structural ensemble substantially improves the docking accuracy of TAR and has led to the identification of six new TAR binders, one of which inhibits HIV-1 replication.

    • Andrew C Stelzer
    • , Aaron T Frank
    •  & Hashim M Al-Hashimi

  • Article |

    A target-identification strategy based on the yeast three-hybrid system and the SNAP-tag labeling technique identifies new targets for three small-molecule drugs and helps identify a new mechanism for the activity of the anti-inflammatory drug sulfasalazine involving inhibition of sepiapterin reductase.

    • Christopher Chidley
    • , Hirohito Haruki
    •  & Kai Johnsson

  • News & Views |

    High-throughput screening in Caenorhabditis elegans identified a compound that distinctly regulates fat storage and feeding, highlighting new players in energy homeostasis.

    • Bridget K Wagner

  • Article |

    A screen for compounds that alter fat content in C. elegans identifies a novel agonist of an AMP-activated kinase pathway that reduces fat storage as well as implicates the transcription factor K08F8.2 as a regulator of fat metabolism.

    • George A Lemieux
    • , Jason Liu
    •  & Zena Werb

  • Brief Communication |

    A potent and selective inhibitor of the kinase LRRK2 identified using an in vitro ATP-site competition binding assay also inhibits the G2019S mutant, implicated in Parkinson's disease, as well as the regulatory feedback loop where LRRK2 is phosphorylated and binds 14-3-3 protein.

    • Xianming Deng
    • , Nicolas Dzamko
    •  & Nathanael S Gray

  • News & Views |

    The development of small-molecule probes for use in neural stem cells demonstrates the importance of endogenous ROS signaling in regulating in vivo phenotypes.

    • Kate S Carroll

  • Article |

    Identifying the cellular targets of small molecules remains a central challenge of chemical biology. The application of an RNAi-based functional genomics approach permitted the clustering of drugs with related targets by 'shRNA signatures', which served as a basis set to assign modes of action to compounds with unknown targets.

    • Hai Jiang
    • , Justin R Pritchard
    •  & Michael T Hemann

  • Commentary |

    Post-transcriptional RNA modifications can be dynamic and might have functions beyond fine-tuning the structure and function of RNA. Understanding these RNA modification pathways and their functions may allow researchers to identify new layers of gene regulation at the RNA level.

    • Chuan He

  • Commentary |

    Rationally designing new strategies to control the human immune response stands as a key challenge for the scientific community. Chemical biologists have the opportunity to address specific issues in this area that have important implications for both basic science and clinical medicine.

    • David A Spiegel

  • Commentary |

    The synthesis and biological annotation of small molecules from underexplored chemical space will play a central role in the development of drugs for challenging targets currently being identified in frontier areas of biological research such as human genetics.

    • Sivaraman Dandapani
    •  & Lisa A Marcaurelle

  • Article |

    Expression of a Huntington's-disease variant of huntingtin protein causes accumulation of the chaperone protein disulfide isomerase. This protein is the target of compounds obtained from screening for those that can alleviate cell death promoted by the mutant huntingtin, and represents a new connection between protein misfolding and cell death.

    • Benjamin G Hoffstrom
    • , Anna Kaplan
    •  & Brent R Stockwell

  • Brief Communication |

    The antiviral S-acyl-2-mercaptobenzamide thioester ejects an essential coordinated zinc ion from and induces aggregation and dysfunction of the HIV-1 nucleocapsid protein NCp7 via repetitive intracellular enzymatic acyl transfers, dependent on acetyl-CoA.

    • Lisa M Miller Jenkins
    • , David E Ott
    •  & Ettore Appella

  • Article |

    A Xenopus laevis two-reporter screen identifies the antihelminthic drug pyrvinium as an inhibitor of the Wnt/β-catenin signaling pathway that works by activating CK1α, which is likely working at the level of Pygopus, a core transcriptional component of the Wnt pathway.

    • Curtis A Thorne
    • , Alison J Hanson
    •  & Ethan Lee

  • Article |

    Secretion of strigolactone from plant roots mediates mutualistic fungal interactions but also facilitates parasitic plant invasion. A screen in Arabidopsis thaliana has identified compounds that perturb strigolactone levels and link this hormone to light signaling pathways in host plants.

    • Yuichiro Tsuchiya
    • , Danielle Vidaurre
    •  & Peter McCourt

  • Article |

    A chemical array screen identifies a small-molecule inhibitor of pirin that inhibits its interaction with the oncoprotein Bcl3 and decreases the expression of the tumor mobility protein SNAI2. As a result, the compound perturbs the migration of melanoma cells that have high pirin expression levels.

    • Isao Miyazaki
    • , Siro Simizu
    •  & Hiroyuki Osada

  • Article |

    Chemical screening in C. elegans is limited by the relatively poor target accessibility of small molecules. A systematic survey of drug-like small molecule accumulation and metabolism in C. elegans was used to create a computational tool for preselecting compounds likely to effectively perturb worms.

    • Andrew R Burns
    • , Iain M Wallace
    •  & Peter J Roy

  • Article |

    Reversible palmitoylation controls the localization and signaling of Ras. Development of a potent and specific small molecule inhibitor of the thioesterase APT1 reveals that this enzyme depalmitoylates Ras in cells. Inhibition of APT1 led to redistribution and altered activity of HRas, NRas and an oncogenic mutant Ras.

    • Frank J Dekker
    • , Oliver Rocks
    •  & Herbert Waldmann

  • News & Views |

    Organic synthesis plays a leading role in the discovery of small molecules for the exploration of biological systems. Therefore, the development of efficient strategies for the preparation of these molecules is a necessary aspect of the small-molecule approach to chemical biology.

    • Damian W Young

  • Article |

    Despite the need for new psychoactive drugs, there are few robust approaches for discovering novel neuroactive molecules. Development of a behavior-based high-throughput screen in zebrafish led to the discovery of molecules with neurological effects. Translating the complex behavioral phenotypes elicited by compounds into a simple barcode enabled identification of their mechanism of action.

    • David Kokel
    • , Jennifer Bryan
    •  & Randall T Peterson

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