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Rewiring cancer drivers to activate apoptosis
A new class of molecules can recruit downstream transcription factors or endogenous cancer drivers to cell death promoters and activate the expression of these genes.
- Sai Gourisankar
- , Andrey Krokhotin
- & Gerald R. Crabtree
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Article |
Intricate 3D architecture of a DNA mimic of GFP
X-ray crystallography and cryo-electron microscopy analyses of Lettuce—a DNA mimic of GFP—bound to various fluorophores reveal previously unknown structures of DNA that rival analogous RNAs in complexity.
- Luiz F. M. Passalacqua
- , Michael T. Banco
- & Adrian R. Ferré-D’Amaré
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Article
| Open Access
Programming inactive RNA-binding small molecules into bioactive degraders
Small-molecule RNA-targeted degradation can be leveraged to convert strong, yet inactive, binding interactions into potent and specific modulators of RNA function.
- Yuquan Tong
- , Yeongju Lee
- & Matthew D. Disney
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Article |
The E3 ligase adapter cereblon targets the C-terminal cyclic imide degron
C-terminal cyclic imides are physiological degrons that enable the ubiquitin E3 ligase adapter protein cereblon to target substrates for degradation.
- Saki Ichikawa
- , Hope A. Flaxman
- & Christina M. Woo
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Article
| Open Access
Structural insights into inhibitor regulation of the DNA repair protein DNA-PKcs
Cryo-electron microscopy structures of DNA-dependent protein kinase catalytic subunit bound to ATPγS and four inhibitors (wortmannin, NU7441, AZD7648 and M3814) provide molecular details and insights useful for drug design.
- Shikang Liang
- , Sherine E. Thomas
- & Tom L. Blundell
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Article |
A condensate-hardening drug blocks RSV replication in vivo
Cyclopamine and its chemical analogue A3E inhibit replication of human respiratory syncytial virus (RSV) by hardening the liquid–liquid phase-separated inclusion bodies, resulting in the inhibition of virus replication in the lungs of RSV-infected mice.
- Jennifer Risso-Ballester
- , Marie Galloux
- & Ralf Altmeyer
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Article |
Large-scale chemical–genetics yields new M. tuberculosis inhibitor classes
A high-throughput chemical–genetic screening approach for the discovery of targets and chemicals to treat Mycobacterium tuberculosis yields tenfold more hit compounds than conventional whole-cell screening methods.
- Eachan O. Johnson
- , Emily LaVerriere
- & Deborah T. Hung
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Article |
Mapping human microbiome drug metabolism by gut bacteria and their genes
High-throughput genetic analyses combined with mass spectrometry reveal that the gene products of diverse human gut bacteria affect a wide range of oral drugs, as well as drug metabolism in mice.
- Michael Zimmermann
- , Maria Zimmermann-Kogadeeva
- & Andrew L. Goodman
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Letter |
Design of amidobenzimidazole STING receptor agonists with systemic activity
A small-molecule agonist for the cGAS–STING pathway has systemic activity in a mouse model of colon cancer.
- Joshi M. Ramanjulu
- , G. Scott Pesiridis
- & John Bertin
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Article |
Commensal bacteria make GPCR ligands that mimic human signalling molecules
Commensal bacteria have N-acyl amide synthase genes that encode signalling molecules (N-acyl amides) that can interact with G-protein-coupled receptors and elicit host cellular responses similar to eukaryotic N-acyl amides.
- Louis J. Cohen
- , Daria Esterhazy
- & Sean F. Brady
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Letter |
Metabolic control of TH17 and induced Treg cell balance by an epigenetic mechanism
Metabolic changes in T cells can affect the genomic methylation status of key transcription factors and regulate the fate decision between induced regulatory T cells and T helper 17 cells.
- Tao Xu
- , Kelly M. Stewart
- & Sheng Ding
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Brief Communications Arising |
Consistency in drug response profiling
- John Patrick Mpindi
- , Bhagwan Yadav
- & Tero Aittokallio
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Brief Communications Arising |
Safikhani et al. reply
- Zhaleh Safikhani
- , Nehme El-Hachem
- & Benjamin Haibe-Kains
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Article |
Diversity-oriented synthesis yields novel multistage antimalarial inhibitors
The bicyclic azetidines, a class of potent, well-tolerated antimalarial compounds that is active against multiple stages of the Plasmodium life-cycle, has been discovered following screens against libraries of compounds reminiscent of natural products.
- Nobutaka Kato
- , Eamon Comer
- & Stuart L. Schreiber
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Letter |
On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models
The small-molecule HIF-2α antagonist PT2399 causes tumour regression in animal models of clear cell renal cell carcinoma, but cell lines of this tumour type show unexpectedly variable responses to PT2399.
- Hyejin Cho
- , Xinlin Du
- & William G. Kaelin
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Letter |
Mediator kinase inhibition further activates super-enhancer-associated genes in AML
A small-molecule inhibitor of the Mediator-associated kinases CDK8 and CDK19 inhibits growth of acute myeloid leukaemia (AML) cells and induces upregulation of super-enhancer-associated genes with tumour suppressor and lineage-controlling functions; Mediator kinase inhibition therefore represents a promising therapeutic approach for AML.
- Henry E. Pelish
- , Brian B. Liau
- & Matthew D. Shair
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Letter |
Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C
Simultaneous disruption of two different protein–protein interactions within the (APC/C–Cdc20)–substrate complex can synergistically inhibit APC/C-dependent proteolysis and mitotic exit.
- Katharine L. Sackton
- , Nevena Dimova
- & Randall W. King
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Article |
Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy
A chemoproteomic screen is used here to identify MTH1 as the target of SCH51344, an experimental RAS-dependent cancer drug; a further search for inhibitors revealed (S)-crizotinib as a potent MTH1 antagonist, which suppresses tumour growth in animal models of colon cancer, and could be part of a new class of anticancer drugs.
- Kilian V. M. Huber
- , Eidarus Salah
- & Giulio Superti-Furga
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Letter |
K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions
Small molecules are developed that irreversibly bind to the common G12C mutant of K-Ras but not the wild-type protein; crystallographic studies reveal the formation of an allosteric pocket that is not apparent in previous Ras studies, and the small molecules shift the affinity of K-Ras to favour GDP over GTP.
- Jonathan M. Ostrem
- , Ulf Peters
- & Kevan M. Shokat
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Letter |
Small molecule inhibition of the KRAS–PDEδ interaction impairs oncogenic KRAS signalling
KRAS is one of the most frequently mutated oncogenes and a major target in anticancer drug discovery, but small molecule modulators that work in the clinic have been elusive; here a new approach to target KRAS is described, based on interfering with its binding to the prenyl-binding protein PDEδ.
- Gunther Zimmermann
- , Björn Papke
- & Herbert Waldmann
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Research Highlights |
Antitumour metabolism
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Research Highlights |
Molecule blocks sperm production
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Research Highlights |
Blind mice can sense light
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Letter |
Small-molecule inhibitors of the AAA+ ATPase motor cytoplasmic dynein
A family of small molecules called ‘ciliobrevins’ are described that can rapidly and reversibly modulate the AAA+ ATPase motor dynein, which transports cargo molecules along microtubule tracks.
- Ari J. Firestone
- , Joshua S. Weinger
- & James K. Chen
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Research Highlights |
Double hit from small molecules
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Letter |
Selective killing of cancer cells by a small molecule targeting the stress response to ROS
- Lakshmi Raj
- , Takao Ide
- & Sam W. Lee
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Research Highlights |
Tagging the TB bacterium
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Research Highlights |
Neuroscience: Memories preserved
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Research Highlights |
Cell biology: Toxin tackle
Targeted protein degradation via intramolecular bivalent glues