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| Open AccessCommunity assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
Resistance to first line treatment is a major hurdle in cancer treatment, that can be overcome with drug combinations. Here, the authors provide a large drug combination screen across cancer cell lines to benchmark crowdsourced methods and to computationally predict drug synergies.
- Michael P. Menden
- , Dennis Wang
- & Julio Saez-Rodriguez
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Article
| Open AccessEngineering brain activity patterns by neuromodulator polytherapy for treatment of disorders
Brain disorders are associated with network dysfunctions that are not addressed by conventional drug screens. Here, the authors use high-throughput functional imaging of brain activity in zebrafish larvae to study the effects of individual drugs on network connectivity and demonstrate an algorithm that predicts the most effective drug combinations to normalize both the activity patterns and the animal behavior.
- Mostafa Ghannad-Rezaie
- , Peter M. Eimon
- & Mehmet Fatih Yanik
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Article
| Open AccessDevelopment of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression
Cyclic GMP-AMP synthase (cGAS) is involved in the modulation of inflammatory responses. Here, the authors present small-molecule inhibitors of human cGAS, characterize their interaction with the protein, and show that the compounds are active in interferon-producing cells including primary human macrophages.
- Lodoe Lama
- , Carolina Adura
- & Thomas Tuschl
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Article
| Open AccessA suite of phenotypic assays to ensure pipeline diversity when prioritizing drug-like Cryptosporidium growth inhibitors
Here, the authors provide a panel of medium-throughput assays to test potential drug candidates against different life cycle stages of Cryptosporidium with the goal to support a drug development pipeline that contains compounds with diverse molecular mechanisms of action.
- Rajiv S. Jumani
- , Muhammad M. Hasan
- & Christopher D. Huston
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Article
| Open AccessProspective discovery of small molecule enhancers of an E3 ligase-substrate interaction
Directed protein degradation to target hard-to-drug proteins is a promising therapeutic approach. Here, the authors report the prospective discovery of small molecule “molecular glue” that inserts into a naturally occurring E3 ligase-substrate interface leading to degradation of substrate protein.
- Kyle R. Simonetta
- , Joshua Taygerly
- & Anjanabha Saha
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Article
| Open AccessA macrophage-based screen identifies antibacterial compounds selective for intracellular Salmonella Typhimurium
Salmonella Typhimurium replicates within host phagocytes. Here, the authors show that a known psychoactive drug (metergoline) inhibits growth of the pathogen in macrophages, disrupts the proton motive force at the bacterial cytoplasmic membrane, and extends animal survival during systemic infection.
- Michael J. Ellis
- , Caressa N. Tsai
- & Eric D. Brown
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Article
| Open AccessIndustrial scale high-throughput screening delivers multiple fast acting macrofilaricides
Parasitic nematodes causing onchocerciasis and lymphatic filariasis rely on a bacterial endosymbiont, Wolbachia, which is a validated therapeutic target. Here, Clare et al. perform a high-throughput screen of 1.3 million compounds and identify 5 chemotypes with faster kill rates than existing anti-Wolbachia drugs.
- Rachel H. Clare
- , Catherine Bardelle
- & Stephen A. Ward
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Article
| Open AccessHost-targeted niclosamide inhibits C. difficile virulence and prevents disease in mice without disrupting the gut microbiota
Clostridium difficile causes diarrhea and colitis by producing up to three different protein toxins. Here, Tam et al. show that an anthelmintic drug, niclosamide, inhibits the pathogenesis of all three toxins by targeting a host process required for toxin entry into host cells, without disrupting the gut microbiota.
- John Tam
- , Therwa Hamza
- & Roman A. Melnyk
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Article
| Open AccessDetermining molecular properties with differential mobility spectrometry and machine learning
The fast and accurate determination of molecular properties is particularly crucial in drug discovery. Here, the authors employ supervised machine learning to treat differential mobility spectrometry – mass spectrometry data for ten classes of drug candidates and predict several condensed-phase properties.
- Stephen W. C. Walker
- , Ahdia Anwar
- & W. Scott Hopkins
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Article
| Open AccessExpression-based drug screening of neural progenitor cells from individuals with schizophrenia
Unbiased large scale screening of small molecules for drug discovery in psychiatric disease is technically challenging and financially costly. Here, Readhead and colleagues integrate in silico and in vitro approaches to design and conduct transcriptomic drug screening in schizophrenia patient-derived neural cells, in order to survey novel pathologies and points of intervention.
- Benjamin Readhead
- , Brigham J. Hartley
- & Kristen J. Brennand
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Article
| Open AccessDRUG-seq for miniaturized high-throughput transcriptome profiling in drug discovery
RNA-seq is a powerful tool to investigate how drugs affect the transcriptome but library construction can be costly. Here the authors introduce DRUG-seq, an automated platform for high-throughput transcriptome profiling.
- Chaoyang Ye
- , Daniel J. Ho
- & Ajamete Kaykas
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Article
| Open AccessInhibition of osteoblastic Smurf1 promotes bone formation in mouse models of distinctive age-related osteoporosis
BMP promotes bone formation but its efficacy is limited in some patients. Here, the authors show that osteoporosis patients with a poor response to BMP have increased expression of Smurf1, which targets BMP effectors for degradation, and demonstrate that its chemical inhibition enhances BMP-mediated bone formation in mice.
- Chao Liang
- , Songlin Peng
- & Ge Zhang
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Article
| Open AccessDiscovery of a drug candidate for GLIS3-associated diabetes
GLIS3 mutations are associated with type 1, type 2, and neonatal diabetes. Here, the authors generate mono-hormonal glucose-responding pancreatic β-like cells in vitro and through a screen identify a drug that rescues pancreatic β-like cell death in GLIS3 mutants by inhibiting the abnormally activated TGFβ pathway.
- Sadaf Amin
- , Brandoch Cook
- & Shuibing Chen
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Article
| Open AccessA small-molecule inhibitor of SOD1-Derlin-1 interaction ameliorates pathology in an ALS mouse model
Amyotrophic lateral sclerosis (ALS) is a neurological disease that leads to loss of voluntary muscle movement. Here, the authors screen for molecules that disrupt interaction between SOD1, a protein linked to ALS, and Derlin-1, and find an inhibitor that reduces pathology in an ALS mouse model.
- Naomi Tsuburaya
- , Kengo Homma
- & Hidenori Ichijo
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Article
| Open AccessImmuno-detection by sequencing enables large-scale high-dimensional phenotyping in cells
Detecting proteins and post-translational modifications is important for drug screens, but the number of proteins measurable simultaneously is limited. Here the authors use antibodies tagged with DNA barcodes and high-throughput sequencing to detect up to 70 (phospho-)proteins in stem cells.
- Jessie A. G. van Buggenum
- , Jan P. Gerlach
- & Klaas W. Mulder
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Article
| Open AccessFibrotic microtissue array to predict anti-fibrosis drug efficacy
A bottleneck in developing new anti-fibrosis therapies is the absence of suitable in vitro models that recapitulate key features of fibrogenesis. Here the authors develop a tissue-on-a-chip model of lung fibrosis and test the therapeutic efficacy of two recent FDA-approved drugs.
- Mohammadnabi Asmani
- , Sanjana Velumani
- & Ruogang Zhao
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Article
| Open AccessTargeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes
Spinal muscular atrophy (SMA) is an autosomal recessive disorder with no present cure. Here the authors perform an in vitro screening leading to the identification of a small molecule that alters the conformational dynamics of the TSL2 RNA structure and acts as a modulator of SMN exon 7 splicing.
- Amparo Garcia-Lopez
- , Francesca Tessaro
- & Leonardo Scapozza
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Article
| Open AccessA comprehensive model for assessment of liver stage therapies targeting Plasmodium vivax and Plasmodium falciparum
Currently available platforms to study liver stage of Plasmodium species have limitations. Here, the authors show that primary human hepatocyte cultures in 384-well format support hypnozoite and other liver stage development and are suitable for drug and antibody screens.
- Alison Roth
- , Steven P. Maher
- & John H. Adams
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Article
| Open AccessAggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target
Aggressive natural killer-cell leukemia (ANKL) has few targeted therapies. Here ANKL patients are reported to harbor STAT3, RAS-MAPK pathway, DDX3X and epigenetic modifier mutations; and drug sensitivity profiling uncovers the importance of the JAK-STAT pathway, revealing potential ANKL therapeutic targets.
- Olli Dufva
- , Matti Kankainen
- & Satu Mustjoki
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Article
| Open AccessA human endothelial cell-based recycling assay for screening of FcRn targeted molecules
The development of IgG and albumin-based therapeutics with increased half-lives needs more efficient screening procedures. Here the authors report a human endothelial cell-based recycling assay enabling screening of IgG and albumin variants without chemical labelling and prior to animal testing.
- Algirdas Grevys
- , Jeannette Nilsen
- & Jan Terje Andersen
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Article
| Open AccessA printable hydrogel microarray for drug screening avoids false positives associated with promiscuous aggregating inhibitors
False positive results significantly slow down the drug discovery process. Here, the authors developed a gel serving as a screening platform in which enzymes can be stored, stabilized, and protected from most of the compounds that typically cause these misleading results.
- Rabia Mateen
- , M. Monsur Ali
- & Todd Hoare
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Correspondence
| Open AccessCorrespondence: Reply to ‘Compound 17b and formyl peptide receptor biased agonism in relation to cardioprotective effects in ischaemia-reperfusion injury’
- Cheng Xue Qin
- , Lauren T. May
- & Rebecca H. Ritchie
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Article
| Open AccessBismuth antimicrobial drugs serve as broad-spectrum metallo-β-lactamase inhibitors
Metallo-β-lactamases (MBL) are zinc containing enzymes that cause resistance to β-lactam antibiotics. Here the authors show that the anti-Helicobacter pylori drug colloidal bismuth subcitrate inhibits MBLs by displacing the zinc ions with Bi(III), which is of great interest for the development of antibiotics.
- Runming Wang
- , Tsz-Pui Lai
- & Hongzhe Sun
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Article
| Open AccessBrain activity patterns in high-throughput electrophysiology screen predict both drug efficacies and side effects
One challenge in drug screening for neurological disorders is how to accurately capture disease pathology and side effects. Here, the authors developed a multi-channel recording platform based on a zebrafish genetic model of epilepsy to screen for antiepileptic drugs.
- Peter M. Eimon
- , Mostafa Ghannad-Rezaie
- & Mehmet Fatih Yanik
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Article
| Open AccessSmall-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan
Activation of autophagy, via the transcription factor TFEB, is a promising strategy to treat metabolic diseases. Here, the authors report three novel classes of small molecules that promote TFEB nuclear translocation, and provide evidence for the therapeutic efficacy of these compounds in mice and worms.
- Chensu Wang
- , Hanspeter Niederstrasser
- & Michael A. White
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Article
| Open AccessSystematic screening of generic drugs for progressive multiple sclerosis identifies clomipramine as a promising therapeutic
Progressive multiple sclerosis is an inflammatory and degenerative disease of the central nervous system, for which effective treatment is lacking. The authors carry out a screen to identify orally available generic medications, and show that the antidepressant clomipramine reduces pathology in mouse models.
- Simon Faissner
- , Manoj Mishra
- & V. Wee Yong
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Article
| Open AccessSmall molecule screen in embryonic zebrafish using modular variations to target segmentation
Chemical screens can identify small molecules that affect biological development, with potential therapeutic value. Here, the authors use a modular approach in a screen in zebrafish embryos, varying concentration, genotype and timing to target segmentation disorders, birth defects that affect the spinal column.
- Sandra Richter
- , Ulrike Schulze
- & Andrew C. Oates
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Article
| Open AccessAssay interference and off-target liabilities of reported histone acetyltransferase inhibitors
A substantial obstacle in basic research is the use of poorly validated tool compounds with purported useful biological functions. Here, the authors systematically profile widely used histone acetyltransferase inhibitors and find that the majority are nonselective interference compounds.
- Jayme L. Dahlin
- , Kathryn M. Nelson
- & Michael A. Walters
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Article
| Open AccessA novel Fer/FerT targeting compound selectively evokes metabolic stress and necrotic death in malignant cells
The tyrosine-kinases Fer/FerT associate with the mitochondrial electron transport chain in cancer cells supporting their metabolic reprogramming. Here the authors discover a compound that disrupts Fer /FerT activity and selectively induces cell death of cancer cell lines displaying anti-tumor activity in vivo.
- Yoav Elkis
- , Moshe Cohen
- & Uri Nir
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Article
| Open AccessHigh-fidelity DNA replication in Mycobacterium tuberculosis relies on a trinuclear zinc center
The polymerase and histidinol phosphatase (PHP) domain in the DNA polymerase DnaE1 is essential for mycobacterial high-fidelity DNA replication. Here, the authors determine the DnaE1 crystal structure, which reveals the PHP-exonuclease mechanism that can be exploited for antibiotic development.
- Soledad Baños-Mateos
- , Anne-Marie M. van Roon
- & Meindert H. Lamers
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Article
| Open AccessSmall molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice
Upon DNA binding cyclic GMP-AMP synthase (cGAS) produces a cyclic dinucleotide, which leads to the upregulation of inflammatory genes. Here the authors develop small molecule cGAS inhibitors, functionally characterize them and present the inhibitor and DNA bound cGAS crystal structures, which will facilitate drug development.
- Jessica Vincent
- , Carolina Adura
- & Manuel Ascano
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Article
| Open AccessIdentification of HSP90 inhibitors as a novel class of senolytics
The accumulation of senescent cells is thought to contribute to the age-associated decline in tissue function. Here, the authors identify HSP90 inhibitors as a new class of senolytic compounds in an in vitro screening and show that administration of a HSP90 inhibitor reduces age-related symptoms in progeroid mice.
- Heike Fuhrmann-Stroissnigg
- , Yuan Yuan Ling
- & Paul D. Robbins
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Article
| Open AccessPLATE-Seq for genome-wide regulatory network analysis of high-throughput screens
Despite the importance of pharmacological and functional genomic screens the readouts are of low complexity. Here the authors introduce PLATE-Seq, a low-cost genome-wide mRNA profiling method to complement high-throughput screening.
- Erin C. Bush
- , Forest Ray
- & Peter A. Sims
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Article
| Open AccessReversal of cancer gene expression correlates with drug efficacy and reveals therapeutic targets
Increased availability of large-scale molecular profiling has enabled system-level monitoring of molecular effects of candidate therapeutics. Here, the authors take advantage of such data to show that the ability of a drug to reverse cancer-associated gene expression changes is indicative of itsin vitroanti-proliferative efficacy, allowing them to identify novel compounds against liver cancer.
- Bin Chen
- , Li Ma
- & Atul J. Butte
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Article
| Open AccessA covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action
PIN1 is a promising therapeutic target for cancer treatment. In this study, the authors identify a covalent inhibitor of PIN1 with anti-tumour and anti-metastatic properties thanks to PIN1 inactivation and to the release, after binding to PIN1, of a quinone-mimicking compound that elicits reactive oxygen generation and causes DNA damage.
- Elena Campaner
- , Alessandra Rustighi
- & Giannino Del Sal
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Article
| Open AccessBlood-brain-barrier spheroids as an in vitro screening platform for brain-penetrating agents
In vitroblood-brain barrier (BBB) models are crucial tools for screening brain-penetrating compounds. Here the authors develop a self-assembling BBB spheroid model with superior performance to the standard transwell BBB model, and use their platform to identify cell-penetrating peptides that can cross the BBB.
- Choi-Fong Cho
- , Justin M. Wolfe
- & Sean E. Lawler
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Article
| Open AccessHundreds of dual-stage antimalarial molecules discovered by a functional gametocyte screen
There is a need forPlasmodium transmission blocking drugs for malaria elimination. Here, Miguel-Blanco et al. screen >10,000 compounds against stage V female gametocytes, identify active compounds belonging to 57 chemotypes and confirm transmission blocking activity of four selected compounds in vitro.
- Celia Miguel-Blanco
- , Irene Molina
- & Esperanza Herreros
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Article
| Open AccessMacrocycle peptides delineate locked-open inhibition mechanism for microorganism phosphoglycerate mutases
River blindness, a disease affecting millions throughout the tropics, is caused by parasitic worms. Here, Yuet al. report the discovery and structural characterization of potent macrocyclic peptide inhibitors of iPGM, a nematode-specific phosphoglycerate mutase, as potential leads for novel antimicrobial agents.
- Hao Yu
- , Patricia Dranchak
- & James Inglese
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Article
| Open AccessInhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer’s disease
Delta-secretases are associated with Alzheimer’s disease (AD) as they cleave both amyloid precursor protein and tau. Here the authors develop a series of orally bioactive small molecule delta-secretase inhibitors and report its therapeutic effects in mouse models of AD.
- Zhentao Zhang
- , Obiamaka Obianyo
- & Keqiang Ye
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Article
| Open AccessDissection of goadsporin biosynthesis by in vitro reconstitution leading to designer analogues expressed in vivo
Goadsporin is an antibacterial peptide highly customized by multiple post-translational modifying enzymes. Here, the authors dissect its biosynthetic pathway byin vitro reconstitution and use their insights to produce goadsporin analogues in vitro and in vivo.
- Taro Ozaki
- , Kona Yamashita
- & Hiroyasu Onaka
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Article
| Open AccessMEK inhibitors block growth of lung tumours with mutations in ataxia–telangiectasia mutated
ATM is a tumor suppressor often mutated in lung adenocarcinoma. In this study, the authors starting from a synthetic lethal screen, demonstrate that tumor cells with mutations in ATM exhibit increased sensitivity to MEK1/2 inhibition through the modulation of the AKT/mTOR pathway.
- Michal Smida
- , Ferran Fece de la Cruz
- & Sebastian M. B. Nijman
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Article
| Open AccessLarge-scale microfluidics providing high-resolution and high-throughput screening of Caenorhabditis elegans poly-glutamine aggregation model
Large-scale screens on whole animals could facilitate drug discovery, but are technically challenging. Here, Mondal et al. develop a microfluidic chip combined with an automated imaging platform that enables high-throughput, high-resolution screening of Caenorhabditis elegansdisease models.
- Sudip Mondal
- , Evan Hegarty
- & Adela Ben-Yakar
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Article
| Open AccessIrreversible inhibitors of the 3C protease of Coxsackie virus through templated assembly of protein-binding fragments
Molecular fragments are useful tools in drug-discovery but they might be hard to identify due to their weak affinity to the targets. Here, the authors use a protein-templated assembly to design high affinity inhibitors of Coxsackie virus 3C protease, a pharmacological target against enteroviral infections.
- Daniel Becker
- , Zuzanna Kaczmarska
- & Jörg Rademann
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Article
| Open AccessLansoprazole is an antituberculous prodrug targeting cytochrome bc1
Tuberculosis control is threatened by the continued emergence of drug-resistant strains. Here, Rybniker et al. screen a library of FDA-approved drugs and identify a gastric proton pump inhibitor that also has antituberculosis activity and targets the bacterial cytochrome bc1complex.
- Jan Rybniker
- , Anthony Vocat
- & Stewart T. Cole
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A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours
It has been proposed that the identification of genes regulating senescence in the absence of PTEN might help develop pro-senescence compounds for the treatment of cancer. Here, the authors use a combination of chemical and shRNA functional screen and identify CK2 as a potential target.
- Madhuri Kalathur
- , Alberto Toso
- & Andrea Alimonti
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Quantitative high throughput screening using a primary human three-dimensional organotypic culture predicts in vivo efficacy
Tumour microenvironment affects the outcome of pharmacological anticancer treatments. Here, Kenny et al. show that organotypic cultures of ovarian cancer cells can recapitulate metastasis. They identify several new compounds that block cancer invasion and metastasis and improve survival in mouse models.
- Hilary A. Kenny
- , Madhu Lal-Nag
- & Ernst Lengyel
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Suppression of the FOXM1 transcriptional programme via novel small molecule inhibition
Overexpression of the FOXM1 transcription factor occurs in several cancer and correlates with poor prognoses. Here, the authors identify a novel small molecule capable of displacing FOXM1 from its DNA consensus motif in vitro, displace it from target promoters and downregulate the expression of its target genes cancer cells.
- Michael V. Gormally
- , Thomas S. Dexheimer
- & Shankar Balasubramanian
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Article
| Open AccessScreening of DUB activity and specificity by MALDI-TOF mass spectrometry
Deubiquitylases (DUBs) remove ubiquitin chains from proteins. Here the authors develop a mass spectrometry-based DUB activity screen using unmodified diubiquitin isomers to characterize substrate specificity for 42 human DUBs, and assess the potency and selectivity of 11 DUB inhibitors.
- Maria Stella Ritorto
- , Richard Ewan
- & Matthias Trost
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Diversity-oriented synthesis as a tool for identifying new modulators of mitosis
Diversity-oriented synthesis is a useful tool to synthesize libraries of structurally complex molecules. Here, the authors show the utility of this method by ultimately identifying a compound causing mitotic arrest and cancer cell death.
- Brett M. Ibbeson
- , Luca Laraia
- & David R. Spring