Target identification

  • Article
    | Open Access

    Although Hippo signaling restricts regeneration in many mammalian organs, the pharmaceutical tools available to modulate the pathway have been limited. Here, the authors report a small molecule that may inhibit a key element in the Hippo cascade and may activate regenerative responses in several mammalian tissues.

    • Nathaniel Kastan
    • , Ksenia Gnedeva
    •  & A. J. Hudspeth
  • Article
    | Open Access

    Arginine addiction induced by argininosuccinate synthase (ASSN1) deficiency has been exploited to treat ASS1-deficient cancers. Here, the authors show an alternative therapeutic approach where ASS1 activity is increased by the pesticide spinosyn A and is shown to inhibit breast cancer cell proliferation.

    • Zizheng Zou
    • , Xiyuan Hu
    •  & Zhiyong Luo
  • Article
    | Open Access

    Prioritising genes as potential drug targets is challenging and often unsuccessful once testing efficacy in humans. Here, the authors propose an approach to identifying drug targets that uses evidence from gain- or loss-of-function mutations associated with bidirectional effects on phenotypes.

    • Karol Estrada
    • , Steven Froelich
    •  & Lon R. Cardon
  • 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

    Mesenchymal stromal cells (MSCs) have been shown to support multiple myeloma (MM) development. Here, MSCs isolated from the bone marrow of MM patients are shown to have altered DNA methylation patterns and a methyltransferase inhibitor reverts MM-associated bone loss and reduces tumour burden in MM murine models.

    • Antonio Garcia-Gomez
    • , Tianlu Li
    •  & Esteban Ballestar
  • Article
    | Open Access

    N-myristoyltransferases (NMTs) target many signaling proteins to membranes. Here the authors show an NMT inhibitor named PCLX-001 selectively kills lymphoma cells by shutting down their main survival signaling pathway and offers an additional treatment strategy for lymphoma patients.

    • Erwan Beauchamp
    • , Megan C. Yap
    •  & Luc G. Berthiaume
  • Article
    | Open Access

    Single-cell metabolomics can offer deep insights into the metabolic reprogramming that accompanies disease states. Here, the authors use Raman spectro-microscopy for non-invasive metabolite analysis and identification of druggable metabolic susceptibilities in single live melanoma cells.

    • Jiajun Du
    • , Yapeng Su
    •  & Lu Wei
  • Article
    | Open Access

    Human enterovirus 71 (EV71) contains an internal ribosome entry site (IRES) that promotes translation of viral RNA. Here the authors show that an antiviral small molecule DMA-135 binds to the EV71 IRES RNA, inducing conformational change and stabilizing a ternary complex to repress translation.

    • Jesse Davila-Calderon
    • , Neeraj N. Patwardhan
    •  & Blanton S. Tolbert
  • Article
    | Open Access

    Coronavirus main protease is essential for viral polyprotein processing and replication. Here Vuong et al. report efficient inhibition of SARS-CoV-2 replication by the dipeptide-based protease inhibitor GC376 and its parent GC373, which were originally used to treat feline coronavirus infection.

    • Wayne Vuong
    • , Muhammad Bashir Khan
    •  & M. Joanne Lemieux
  • Article
    | Open Access

    Depletion of tribbles pseudokinase 3 (TRIB3) is known to suppress the expression of several tumor-promoting factors, including EGFR. Here, the authors show that TRIB3 interacts with EGFR and regulates its stability and activity, and perturbing EGFR-TRIB3 interaction attenuates NSCLC progression by accelerating EGFR degradation.

    • Jiao-jiao Yu
    • , Dan-dan Zhou
    •  & Zhuo-Wei Hu
  • Article
    | Open Access

    Information developed to understand the molecular mechanisms of SARS-CoV-2 infection for predicting drug repurposing candidates is time-consuming to integrate and explore. Here, the authors develop an interactive online platform for virus-host interactome exploration and drug (target) identification.

    • Sepideh Sadegh
    • , Julian Matschinske
    •  & Jan Baumbach
  • Article
    | Open Access

    Biosynthesis of glycosylphosphatidylinositol (GPI) is essential for the integrity of the fungal cell wall. Here, the authors show that the natural product jawsamycin inhibits GPI biosynthesis by targeting a subunit of the fungal UDP-glycosyltransferase, and displays pronounced activity against pathogenic fungi of the order Mucorales.

    • Yue Fu
    • , David Estoppey
    •  & Dominic Hoepfner
  • Article
    | Open Access

    PDE3A modulators for cancer therapy cause serious side effects as they inhibit PDE3A phosphodiesterase activity, which is essential for the maturation of oocytes and the formation of platelets. Here, the authors identify a compound, nauclefine, that does not inhibit PDE3A activity but induces apoptosis by enabling a complex formation between PDE3A and SLFN12.

    • Youwei Ai
    • , Haibing He
    •  & Xiangbing Qi
  • Article
    | Open Access

    Constitutive Btk signaling drives several B-cell cancers. Here the authors demonstrate key allosteric intramolecular interactions between the SH2 domain and the kinase domain of Btk, and propose an alternative approach for inhibition of both wild-type and tyrosine kinase inhibitor-resistant Btk.

    • Daniel P. Duarte
    • , Allan J. Lamontanara
    •  & Oliver Hantschel
  • Article
    | Open Access

    Drugs targeting dysregulated ERK1/2 signaling can cause severe cardiac side effects, precluding their wide therapeutic application. Here, a new and cardio-safe targeting strategy is presented that interferes with ERK dimerization to prevent pathological ERK1/2 signaling in the heart and cancer.

    • Angela Tomasovic
    • , Theresa Brand
    •  & Kristina Lorenz
  • Article
    | Open Access

    It has been shown that the bioactive component of pyrazinamide, pyrazinoic acid (POA), blocks coenzyme A biosynthesis in M. tuberculosis by binding to the aspartate decarboxylase PanD. Here the authors show that pyrazinamide triggers degradation of PanD by stimulating its degradation by the caseinolytic protease Clp.

    • Pooja Gopal
    • , Jickky Palmae Sarathy
    •  & Thomas Dick
  • Article
    | Open Access

    The mechanism of action of daptomycin, a lipopeptidic antibiotic, is unclear. Here, the authors show that Ca2+-daptomycin simultaneously interacts with lipid-coupled precursors of the bacterial cell envelope and with the anionic phospholipid phosphatidylglycerol, forming a tripartite complex.

    • Fabian Grein
    • , Anna Müller
    •  & Tanja Schneider
  • Article
    | Open Access

    Quantitative profiling of small molecule-protein binding in cells can aid basic biochemical research and drug discovery. Here, the authors develop the Heat Shock Protein Inhibition Protein Stability Assay (HIPStA) as a high-throughput method to assess cellular target engagement and identify new drug targets.

    • Kelvin F. Cho
    • , Taylur P. Ma
    •  & Robert A. Blake
  • Article
    | Open Access

    The important tuberculosis drug pyrazinamide (PZA) is converted to its active form pyrazinoic acid (POA) in Mycobacterium tuberculosis (Mtb). Here the authors identify the pantothenate biosynthesis pathway enzyme aspartate decarboxylase (PanD) as the target of PZA and determine the POA bound Mtb PanD crystal structure.

    • Qingan Sun
    • , Xiaojun Li
    •  & James C. Sacchettini
  • Article
    | Open Access

    Trypanosoma brucei relies on uptake and conversion of purines from the host, which constitutes a potential drug target. Here, Hulpia et al. combine structural elements from known trypanocidal nucleoside analogues and develop a potent trypanocide with curative activity in animal models of acute and late stage sleeping sickness.

    • Fabian Hulpia
    • , Dorien Mabille
    •  & Serge Van Calenbergh
  • Article
    | Open Access

    Drug target identification is a crucial step in drug development. Here, the authors introduce a Bayesian machine learning framework that integrates multiple data types to predict the targets of small molecules, enabling identification of a new set of microtubule inhibitors and the target of the anti-cancer molecule ONC201.

    • Neel S. Madhukar
    • , Prashant K. Khade
    •  & Olivier Elemento
  • Article
    | Open Access

    Amino acid biosynthetic pathways are an attractive alternative to treat chronic infections such as Mycobacterium tuberculosis (Mtb). Here, the authors investigate the metabolic response to disruption of the aspartate pathway in persistent Mtb and identify essential enzymes as potential new targets for drug development.

    • Erik J. Hasenoehrl
    • , Dannah Rae Sajorda
    •  & Michael Berney
  • Article
    | Open Access

    Transcription factors are critical regulators of cell identity. Here, the authors use computational and functional genomic approaches to show an oncogenic role of PAX8 in renal cancer. Mechanistic dissection of PAX8 functions reveal its role in activating genes associated with metabolic pathways.

    • Melusine Bleu
    • , Swann Gaulis
    •  & Giorgio G. Galli
  • Article
    | Open Access

    Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate determining step for NAD+ synthesis and is of interest as a drug target. Here the authors identify and characterize a small molecule NAMPT activator SBI-797812, elucidate its mode of action and show that it increases intracellular NMN and NAD+ levels in cultured cells and elevates liver NAD+ in mice.

    • Stephen J. Gardell
    • , Meghan Hopf
    •  & Anthony B. Pinkerton
  • Article
    | Open Access

    Membrane proteins have been implicated in cancers, but studying the downstream effects of their perturbation remains challenging. Here, the authors map the membrane protein-regulated network of 15 cancers, a resource for prognostic biomarker development and druggable target identification.

    • Chun-Yu Lin
    • , Chia-Hwa Lee
    •  & Jinn-Moon Yang
  • Article
    | Open Access

    The use of nonsteroidal anti-inflammatory drugs inhibiting COX-1/2 is associated with an increased risk of heart failure. Here the authors show that mPGES-1, a therapeutic target downstream of COX enzymes, protects from cardiac ischemia/reperfusion injury, limiting leukocyte-endothelial interactions and preserving microvascular perfusion partly via the endothelial EP4 receptor.

    • Liyuan Zhu
    • , Chuansheng Xu
    •  & Miao Wang
  • Article
    | Open Access

    Combination therapy holds great promise, but discovery remains challenging. Here, the authors propose a method to identify efficacious drug combinations for specific diseases, and find that successful combinations tend to target separate neighbourhoods of the disease module in the human interactome.

    • Feixiong Cheng
    • , István A. Kovács
    •  & Albert-László Barabási
  • Article
    | Open Access

    Heterologous production of the glycocins, posttranslationally modified peptide bacteriocins containing a sugar moiety, has not been achieved. Here, the authors express a thermophilic bacterium glycocin biosynthetic gene cluster and S-glycosyltransferase for the production of antibacterial glycocins in E. coli.

    • Arnoldas Kaunietis
    • , Andrius Buivydas
    •  & Oscar P. Kuipers
  • Article
    | Open Access

    Mother Nature is a valuable resource for the discovery of drug and agricultural chemicals. Here, the authors show that 7-deoxy-sedoheptulose produced by a cyanobacterium is an antimicrobial and herbicidal compound that acts through inhibition of 3-dehydroquniate synthase in the shikimate pathway.

    • Klaus Brilisauer
    • , Johanna Rapp
    •  & Karl Forchhammer
  • Article
    | Open Access

    Genetic screens are important tools to identify host factors associated with viral infections. Here, Flint et al. perform a genome-wide CRISPR screen using infectious Ebola virus (EBOV) and show that the host transferase GNPTAB is required for EBOV infection and a potential target for antiviral therapies

    • Mike Flint
    • , Payel Chatterjee
    •  & Christina F. Spiropoulou
  • Article
    | Open Access

    Viruses rely on host cell metabolism for replication, making these pathways potential therapeutic targets. Here, the authors show that AM580, a retinoid derivative and RAR-α agonist, affects replication of several RNA viruses by interfering with the activity of SREBP.

    • Shuofeng Yuan
    • , Hin Chu
    •  & Kwok-Yung Yuen
  • Article
    | Open Access

    Direct targeting of mutant KRas is challenging and alternative approaches are needed. Here they show glycogen synthase kinase 3 (GSK3) to be required for the growth and survival of human mutant KRas-dependent tumors but dispensable for mutant KRas-independent tumors and show GSK3 inhibition to inhibit in vivo growth of Kras mutant patient-derived pancreatic tumors.

    • Aslamuzzaman Kazi
    • , Shengyan Xiang
    •  & Saïd M. Sebti
  • Article
    | Open Access

    Myotubular myopathy is a severe muscle disease for which no effective treatment exists. Here, the authors show that tamoxifen ameliorates pathology and extends survival in a mouse model of the disease, and that the effect is mediated via estrogen receptor signaling and involves modulation of DNM2 expression.

    • Nika Maani
    • , Nesrin Sabha
    •  & James J. Dowling
  • Article
    | Open Access

    The identification of new drug targets is highly challenging, particularly for diseases of the brain. This study describes a general computational gene regulatory framework called CRAFT for drug target discovery, and the authors use CRAFT to identify the microglial membrane receptor Csf1R as a potential therapeutic target for epilepsy.

    • Prashant K. Srivastava
    • , Jonathan van Eyll
    •  & Michael R. Johnson
  • 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

    G-protein coupled receptors (GPCRs) represent the largest receptor family and are prime drug targets, but many orphan GPCRs are poorly characterized. Here authors engineer human orphan GPCRs to be activated by light which allows studying the receptors ligand identity and downstream signaling.

    • Maurizio Morri
    • , Inmaculada Sanchez-Romero
    •  & Harald Janovjak
  • Article
    | Open Access

    Technologies for identifying receptor-ligand pairs on living cells at physiological conditions remain scarce. Here, the authors develop a mass spectrometry-based ligand receptor capture technology that can identify receptors for a diverse range of ligands at physiological pH with as few as a million cells.

    • Nadine Sobotzki
    • , Michael A. Schafroth
    •  & Bernd Wollscheid
  • Article
    | Open Access

    Patients suffering from congenital nephrogenic diabetes insipidus (NDI) fail to concentrate urine due to mutations in vasopressin type 2 receptor (V2R). Here Ando et al. show that agents disrupting the interaction between PKA and AKAPs restore aquaporin-2 activity downstream of V2R, offering a therapeutic approach for the treatment of NDI.

    • Fumiaki Ando
    • , Shuichi Mori
    •  & Shinichi Uchida