Small molecules articles within Nature Chemical Biology

Featured

  • News & Views |

    Reliably identifying ubiquitin ligase interactors and substrates has been a persistent challenge in cellular biology. A breakthrough comes in the form of a potent, selective and cell-active chemical probe, shedding light on the intricate functions of a key regulatory enzyme.

    • Shaoshuai Xie
    •  & Gang Li

  • Comment |

    AlphaFold is a breakthrough in protein structure prediction, but limitations in its application to computation- and structure-guided drug discovery remain. As with structure prediction, public-domain data and benchmarking initiatives will be essential to advance the field of computational drug design.

    • Matthieu Schapira
    • , Levon Halabelian
    •  & Rachel J. Harding

  • News & Views |

    Kir4.1 potassium channels expressed in astroglial cells critically regulate extracellular potassium concentration in the brain. A new study reports that blocking the flow of potassium ions into astrocytes by inhibiting Kir4.1 induces rapid-onset antidepressive effects in rodents.

    • Jerod S. Denton

  • News & Views |

    Inhibitors of KRAS G12C have shown that directly targeting RAS is possible, but G12C is only one of many RAS driver mutations. Covalent targeting of another major variant, G12D, raises hope for treating other groups of patients with KRAS-mutant tumors.

    • Kenneth Westover

  • News & Views |

    Chemically reactive metabolites such as formaldehyde are often toxic and are proposed to react promiscuously with biomolecules. New work shows that some reactive sites on proteins are uniquely sensitive to formaldehyde, leading to functionally important regulation of protein and cell functions.

    • Vicki L. Emms
    • , Sara Y. Chothia
    •  & Richard J. Hopkinson

  • Article
    | Open Access

    A proteome-wide thermal profiling study of osmolyte action on E. coli and human proteins within the cellular milieu reveals mechanisms of protein thermal stabilization by osmolytes and in situ behavior of intrinsically disordered proteins.

    • Monika Pepelnjak
    • , Britta Velten
    •  & Paola Picotti

  • News & Views |

    Transporters and channels have strong potential as drug targets, but drug discovery targeting these membrane-embedded molecules is challenging. Fragment-based ligand discovery combined with chemical proteomics offers a promising solution to the search for inhibitors of solute transporter family members.

    • Noriko Toyama-Sorimachi

  • Review Article |

    Sulfated compounds produced collaboratively by the microbiome and the host have important biological functions. This Review highlights the production of select sulfated carbohydrates, amino acid derivatives and steroidal metabolites and discusses their influence on health. The Review also explore potential roles of sulfated molecules in disease detection, prevention and treatment.

    • Gabriel D. D’Agostino
    • , Snehal N. Chaudhari
    •  & A. Sloan Devlin

  • News & Views |

    The K+ ion channel KCNQ2 modulates neuronal excitability and is targeted by retigabine, an anti-epileptic drug that enhances the probability of channel opening. New activators have now been discovered to increase unitary conductance through an unprecedented mechanism.

    • Jun Chen
    •  & Michael C. Sanguinetti

  • Article |

    A disulfide tethering screen identified a molecule that covalently interacts with pro-apoptotic BAX at C126, inhibiting its activation.

    • Matthew W. McHenry
    • , Peiwen Shi
    •  & Loren D. Walensky

  • News & Views |

    Screening of a chemical library identifies a novel ferroptosis inhibitor that directly interferes with the formation of intracellular membrane contacts between the endoplasmic reticulum (ER) and mitochondria (ERMCS), commonly referred to as mitochondria-associated membranes (MAMs).

    • Junsheng Chen
    • , Tadashi Makio
    •  & Thomas Simmen

  • Article |

    A chemoproteomic workflow was developed to determine the interaction sites of photoaffinity probes in cells, enabling the identification of diverse binding pockets and providing evidence of their tractability to small-molecule action.

    • Jacob M. Wozniak
    • , Weichao Li
    •  & Christopher G. Parker

  • News & Views |

    Small molecules and drugs are not homogenously distributed across cells, and are instead enriched in distinct subcellular compartments and membraneless biomolecular condensates. A new study lays out the path to identifying chemical features or ‘rationales’ that confer condensate-selective partitioning of small molecules.

    • Aseem Z. Ansari

  • Article
    | Open Access

    A chemical screen identified a small molecule inhibitor of CHEK2 that boosts insulin secretion in human β cells, including those from both healthy and type 2 diabetic human islets, as well as in diabetic mouse models and cynomolgus macaques.

    • Angie Chi Nok Chong
    • , J. Jeya Vandana
    •  & Shuibing Chen

  • News & Views |

    DNA-encoded libraries are a powerful tool to identify novel chemical inducers of proximity such as targeted protein degraders, even without a known binder for the target protein.

    • Andrea Testa

  • Article |

    NOXs are vital ROS-producing enzymes with roles in cell function and cancer. Here the authors combine computational and experimental methods to validate inhibitors for human NOX enzymes, opening avenues for redox biology-related cancer drug development.

    • Joana Reis
    • , Christoph Gorgulla
    •  & Andrea Mattevi

  • News & Views |

    Activation of STING-dependent signal transduction results in adaptive immune responses that promote antitumor immunity. A recent study has identified a small-molecule STING agonist that functions by binding to a newly discovered ligandable site to induce high-order STING oligomerization.

    • Ariana Sulpizio
    •  & Luke L. Lairson

  • Article
    | Open Access

    A cell-based phenotypic screen led to the discovery of compounds called NVS-STGs, which bind to the N-terminal domain of STING and act as a molecular glue to induce higher-order oligomerization and activation.

    • Jie Li
    • , Stephen M. Canham
    •  & Yan Feng

  • Article
    | Open Access

    Detailed analysis of the structure–activity relationship for cyclin K degraders reveals diverse compounds that acquire glue activity through simultaneous binding to the CDK12 kinase pocket and engagement of several key DDB1 interfacial residues.

    • Zuzanna Kozicka
    • , Dakota J. Suchyta
    •  & Nicolas H. Thomä

  • News & Views |

    Cryo-EM structures of chemical-compound-bound α-synuclein amyloid fibrils shed light on the mechanism by which small molecules bind to cross-beta-sheet amyloid structures, opening the gateway to rational drug design for targeting pathological amyloid assemblies.

    • Javier Garcia-Pardo
    •  & Salvador Ventura

  • News & Views |

    Brassinosteroid (BR) hormones promote root growth by controlling meristem size and cell elongation, but the mechanism of BR transport remains elusive. A new study shows that BR precursors move via intercellular pores called plasmodesmata to modulate BR cellular levels and their signaling functions.

    • Yoselin Benitez-Alfonso
    •  & Ana I. Caño-Delgado

  • News & Views |

    A new platform for screening nucleophilic-fragment-based covalent ligands enables the identification and targeting of ligandable sulfenic acid sites, setting the stage for exploration of nucleophile-directed probe and drug development.

    • Daniel W. Bak

  • Article |

    Chemoproteomics reveals a vast expanse of ligandable cysteine sulfenic acids in the human proteome, highlighting the utility of nucleophilic small molecules in the fragment-based covalent ligand discovery pipeline.

    • Ling Fu
    • , Youngeun Jung
    •  & Kate S. Carroll

  • News & Views |

    A study of drug-resistant lymphomas with hypermorphic mutations in PRC2 has identified a ‘methylation index’ by which cancer cells maintain optimal H3K27me3 levels for survival, emphasizing the importance of understanding how tumors adapt to changes in chromatin and to drug-resistance mutations.

    • Tyler J. Reich
    •  & Peter W. Lewis

  • Article |

    Profiling the resistance landscape to PRC2 inhibitors in EZH2-mutant lymphoma with CRISPR-suppressor scanning reveals drug addiction mutations and a repressive methylation ceiling. Surpassing the ceiling with SETD2 inhibition halts lymphoma growth.

    • Hui Si Kwok
    • , Allyson M. Freedy
    •  & Brian B. Liau

  • Article |

    Integrated phenotypic screening and activity-based protein profiling identifies small molecules that decrease the expression of oncogenic transcription factors and suppress cancer cell growth by covalently targeting the RNA-binding protein NONO.

    • Stefan G. Kathman
    • , Seong Joo Koo
    •  & Benjamin F. Cravatt

Browse broader subjects

Browse Small molecules across other nature.com journals