Target validation

  • Article
    | Open Access

    Despite being studied in clinical trials, CETP inhibitors are not yet an approved treatment for coronary heart disease. Here, by analyzing results from clinical trials and drug target mendelian randomization studies, the authors demonstrate that previous failure of CETP inhibitors are likely compound and not drug target-related.

    • Amand F. Schmidt
    • , Nicholas B. Hunt
    •  & Chris Finan
  • Article
    | Open Access

    IRF5 is a potential target for therapy in systemic lupus erythematosus (SLE). Here the authors show using mouse SLE-like models that genetic or chemical inhibition of IRF5 after SLE onset could be more effective than, or an add on for, currently utilised type I interferon inhibition.

    • Tatsuma Ban
    • , Masako Kikuchi
    •  & Tomohiko Tamura
  • Article
    | Open Access

    Activation of cullin-RING ligases can be inhibited by targeting DCN1, but selective DCN1 inhibitors with in vivo activity are lacking. Here, the authors develop covalent DCN1 inhibitors that selectively and potently inhibit cullin-3 activation and downstream functions in cells and in mice.

    • Haibin Zhou
    • , Jianfeng Lu
    •  & Shaomeng Wang
  • Article
    | Open Access

    Bafilomycin A1, a member of macrolide antibiotics and an autophagy inhibitor, serves as a specific and potent V-ATPases inhibitor. Here authors report the cryo-EM structure of bafilomycin A1-bound V-ATPase with six bafilomycin A1 molecules bound to the c-ring and reveal the molecular basis for Bafilomycin A1 inhibition of the V-ATPase.

    • Rong Wang
    • , Jin Wang
    •  & Xiaochun Li
  • Article
    | Open Access

    There is an unmet clinical need to identify therapeutic options for the treatment of pancreatic cancer (PDAC). Here the authors present a systematic screening approach for the identification of potential PDAC cell surface target candidates for CAR-T cell based immunotherapy, followed by their functional validation in preclinical models.

    • Daniel Schäfer
    • , Stefan Tomiuk
    •  & Olaf Hardt
  • Article
    | Open Access

    The BCL-2 family protein BAX functions to regulate mitochondria-driven cell death. Here the authors show that the drug Eltrombopag inhibits BAX and prevents apoptosis induced by cytotoxic stimuli.

    • Adam Z. Spitz
    • , Emmanouil Zacharioudakis
    •  & Evripidis Gavathiotis
  • Article
    | Open Access

    PARP1 is the target of clinically approved anti-cancer drugs whose in vivo efficacy has been hard to predict. Here the authors show how an altered active site formed between PARP1 and Histone PARylation Factor 1 (HPF1) changes the efficacy of some of these inhibitors.

    • Johannes Rudolph
    • , Genevieve Roberts
    •  & Karolin Luger
  • Article
    | Open Access

    Unlike RORα, which has been thought to be somewhat redundant, RORγt has been well characterized in its function and contribution to the development of Th17 cells. Here the authors show that RORα is important in Th17 differentiation and that RORα deletion or a small molecule inhibitor of RORα can reduce disease in EAE and colitis mouse models.

    • Ran Wang
    • , Sean Campbell
    •  & Laura A. Solt
  • Article
    | Open Access

    The dTAG system is used to rapidly deplete tagged target proteins in vitro and in vivo, but there are context- and protein-specific differences in its effectiveness. Here, the authors develop a second generation dTAG molecule that can degrade previously recalcitrant target proteins in cells and mice.

    • Behnam Nabet
    • , Fleur M. Ferguson
    •  & Nathanael S. Gray
  • Article
    | Open Access

    FDA-approved RAF inhibitors poorly inhibit BRAF dimers, which limits their clinical efficacy in tumors expressing BRAFV600E mutant monomers. Here the authors identify FDA-approved Ponatinib as an effective inhibitor of BRAF monomers and dimers and designed PHI1, an inhibitor with a unique mode of action and selectivity for oncogenic BRAF dimers.

    • Xiomaris M. Cotto-Rios
    • , Bogos Agianian
    •  & Evripidis Gavathiotis
  • Article
    | Open Access

    Mendelian randomisation (MR) analysis of drug targets has potential to aid drug development. Here, the authors introduce a mathematical framework to elucidate this specific application of MR.

    • Amand F. Schmidt
    • , Chris Finan
    •  & Aroon D. Hingorani
  • Article
    | Open Access

    The SARS-CoV-2 3CL main protease (3CL Mpro) is a chymotrypsin-like protease that facilitates the production of non-structural proteins, which are essential for viral replication and is therefore of great interest as a drug target. Here, the authors present the 2.30 Å room temperature crystal structure of ligand-free 3CL Mpro and compare it with the earlier determined low-temperature ligand-free and inhibitor-bound crystal structures.

    • Daniel W. Kneller
    • , Gwyndalyn Phillips
    •  & Andrey Kovalevsky
  • Article
    | Open Access

    Protein arginine methyltransferases (PRMTs) are increasingly recognized as potential therapeutic targets but PRMT7 remains an understudied member of this enzyme family. Here, the authors develop a chemical probe for PRMT7 and apply it to elucidate the role of PRMT7 in the cellular stress response.

    • Magdalena M. Szewczyk
    • , Yoshinori Ishikawa
    •  & Dalia Barsyte-Lovejoy
  • Article
    | Open Access

    Taccalonolide microtubule stabilizers covalently bind β-tubulin and overcome taxane resistance mechanisms. Here, the authors synthesized fluorogenic taccalonolide probes and investigated the specificity of taccalonolide binding to β-tubulin and the molecular interactions between drug and target,

    • Lin Du
    • , Samantha S. Yee
    •  & April L. Risinger
  • Article
    | Open Access

    Several cancers harbour mutant p53 and express higher levels of p53-derived peptide-MHCs. Here, the authors report affinity matured human antibody, P1C1TM, specific for the p53125-134 peptide in complex with the HLA-A24 class I MHC molecule and show its efficacy and specificity for mutant p53 expressing tumours.

    • Lionel Low
    • , Angeline Goh
    •  & Cheng-I Wang
  • Article
    | Open Access

    A key challenge is to find/re-purpose approved drugs that could be used in humans to induce autophagy-associated clearance of neurodegenerative proteins. Here, authors demonstrate that felodipine, an anti-hypertensive drug, can induce autophagy and clear a variety of aggregated neurodegenerative disease-associated proteins in mouse brains at plasma concentrations similar to those that would be seen in humans taking the drug.

    • Farah H. Siddiqi
    • , Fiona M. Menzies
    •  & David C. Rubinsztein
  • Article
    | Open Access

    The chaperone Hsp90 is a potential target for the development of drugs against fungal pathogens. Here the authors determine the structure of the Hsp90 nucleotide-binding domain from Candida albicans, which they use to design an inhibitor and demonstrate its selectivity for the fungal enzyme, both biochemically and in cells.

    • Luke Whitesell
    • , Nicole Robbins
    •  & Leah E. Cowen
  • Article
    | Open Access

    The small molecule oridonin (Ori) from the traditional Chinese herb Rabdosia rubescens has anti-inflammatory activity. Here the authors show that Ori can be covalently linked to NLRP3 to prevent assembly of the NLRP3 inflammasome, and to ameliorate inflammation in several mouse disease models.

    • Hongbin He
    • , Hua Jiang
    •  & Rongbin Zhou
  • Article
    | Open Access

    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
  • Article
    | Open Access

    Piperaquine (PPQ) resistance of Plasmodium is an increasing problem. Here, Bopp et al. find a bimodal dose−response curve of Cambodian isolates exposed to PPQ, with the area under the curve correlating with in vitro PPQ resistance, and show the importance of Plasmepsin II–III copy number to PPQ resistance.

    • Selina Bopp
    • , Pamela Magistrado
    •  & Sarah K. Volkman
  • Article
    | Open Access

    Triple negative breast cancers harbor multiple copy number aberrations driving gene expression changes thought to underpin their malignant phenotypes. Here the authors integrate these features, finding and functionally validating 37 gene addictions among which they identify the mechanism of addiction to KIFC1, a potential selective drug target.

    • Nirmesh Patel
    • , Daniel Weekes
    •  & Andrew N. J. Tutt
  • Article
    | Open Access

    Aberrant mTORC1 signaling is linked to several chronic diseases. Here, the authors develop a small molecule inhibitor that binds the small G-protein Rheb and selectively blocks mTORC1 signaling, holding potential for therapeutic applications.

    • Sarah J. Mahoney
    • , Sridhar Narayan
    •  & Eddine Saiah
  • Article
    | Open Access

    Cancer therapy drugs are designed to target genetic vulnerabilities, but loss-of-function screens often fail to identify essential genes in drug mechanism studies. Here the authors demonstrate CRISPRres, which exploits in-frame variation generated by indel formation to discover gene-drug interactions.

    • Jasper Edgar Neggers
    • , Bert Kwanten
    •  & Dirk Daelemans
  • Article
    | Open Access

    NUDIX hydrolases are an important family of nucleotide-metabolizing enzymes. Here, the authors identify potent, small molecule inhibitors of NUDT5, which is implicated in ADP-ribose and 8-oxo-guanine metabolism, and confirm its role in gene regulation and proliferation in breast cancer cells.

    • Brent D. G. Page
    • , Nicholas C. K. Valerie
    •  & Thomas Helleday
  • Article
    | Open Access

    Clinical trials of BAFF blockade with belimumab have shown partial efficacy for the treatment of systemic lupus erythematosus (SLE), so other therapeutic options are required. Here, the authors present a new small molecule inhibitor that targets NIK with a similar efficacy to BAFF inhibition in two mouse models of SLE.

    • Hans D. Brightbill
    • , Eric Suto
    •  & Nico Ghilardi
  • Article
    | Open Access

    Cullins are central components of the ubiquitin-proteosome system and are activated via a neddylation process mediated by the DCN1–UBC12 complex. Here, the authors develop a small molecule inhibitor of the DCN1–UBC12 interaction that specifically blocks cullin 3 neddylation and can be used to probe the cellular function of cullin 3.

    • Haibin Zhou
    • , Jianfeng Lu
    •  & Shaomeng Wang
  • Article
    | Open Access

    BET proteins bind chromatin through their bromodomains (BDs) to regulate transcription and chromatin remodelling. Here, the authors show that the BET protein Bdf1 is essential for the fungal pathogenCandida albicans, and report compounds that inhibit the Bdf1 BDs with high selectivity over human BDs.

    • Flore Mietton
    • , Elena Ferri
    •  & Carlo Petosa
  • Article
    | Open Access

    The enzyme Atgl participates in the breakdown of lipids in adipose tissue. Here the authors show that pharmacological inhibition of Atgl reduces weight gain and improves metabolic health in mice fed a high-fat diet, without causing adverse effects in cardiac muscle associated with genetic depletion ofAtgl.

    • Martina Schweiger
    • , Matthias Romauch
    •  & Rudolf Zechner
  • Article
    | Open Access

    CB2 receptor agonists are developed as potential analgesics or immune-modulatory compounds. Here, the authors characterize the pharmacological properties of widely used CB2 receptor agonists and antagonists, recommending three that appear most suitable for in vitro and in vivostudies.

    • Marjolein Soethoudt
    • , Uwe Grether
    •  & Mario van der Stelt
  • Article
    | Open Access

    Prostate cancers often become castration resistant due to alternative expression of androgen receptor (AR) splice variants. Here, the authors screened a library of natural compounds and identified Ailanthone as a potent inhibitor of AR through its binding to the co-chaperone protein p23 that, by preventing AR interaction with HSP90, results in ubiquitin/proteasome-mediated degradation of the receptor.

    • Yundong He
    • , Shihong Peng
    •  & Mingyao Liu
  • Article
    | Open Access

    Small molecule probes used to trigger hypoxic response by activating hypoxia inducible factors (HIFs) often lack specificity. Here the authors report a potent small molecule inhibitor that induces hypoxic response by blocking VHL:HIF interactions, providing a selective route to probe hypoxic signalling.

    • Julianty Frost
    • , Carles Galdeano
    •  & Alessio Ciulli
  • Article
    | Open Access

    Dysregulation of protein degradation by the ubiquitin-proteasome system is a feature commonly associated with cancer. Here, the authors develop an orally available small molecule that inhibits CSN5, the proteolytic subunit of the COP9 signalosome, and blocks tumour growth in a xenograft model.

    • Anita Schlierf
    • , Eva Altmann
    •  & Bruno Martoglio
  • Article
    | Open Access

    Leishmania donovani is a protozoan parasite that can cause fatal infections in humans. Here the authors present a high resolution cryoEM structure of the L. donovani80S ribosome and compare it to its human counterpart to provide insight into the basis for drug selectivity towards this eukaryotic parasite.

    • Xing Zhang
    • , Mason Lai
    •  & Z. Hong Zhou
  • Article
    | Open Access

    Drugs therapeutic efficacy relies on their capability of binding the relevant targets in a physiological environment, which has so far been hard to measure. Here, the authors present a compound library screen based on a target engagement assay that reports on protein stability upon ligands binding in cell.

    • Helena Almqvist
    • , Hanna Axelsson
    •  & Pär Nordlund
  • Article
    | Open Access

    The malaria parasite Plasmodium falciparum utilizes thiamine for the production of essential enzymatic cofactors. Chan et al. show that inhibition of thiamine utilization with oxythiamine inhibits proliferation of P. falciparumand reduces parasite growth in a mouse model of malaria infection.

    • Xie Wah Audrey Chan
    • , Carsten Wrenger
    •  & Kevin J. Saliba