Target validation articles within Nature Communications

Featured

• Article
  29 February 2024 | Open Access

  Specificity, synergy, and mechanisms of splice-modifying drugs

  Two small-molecule drugs, risdiplam and branaplam, have been developed for treating spinal muscular atrophy. Here the authors develop quantitative modeling methods for the sequence-specific and concentration-dependent effects of these and other splice-modifying drugs.

  • Yuma Ishigami
  • , Mandy S. Wong
  •  & Justin B. Kinney

• Article
  26 February 2024 | Open Access

  Targeting HDAC6 to treat heart failure with preserved ejection fraction in mice

  HFpEF has few effective treatments. Here, the authors show that inhibition of histone deacetylase 6 (HDAC6) with TYA-018 reverses established HFpEF symptoms in mice, comparably to the use of a sodium-glucose cotransporter 2 inhibitor; highlighting HDAC6 as a potential target to treat HFpEF.

  • Sara Ranjbarvaziri
  • , Aliya Zeng
  •  & Jin Yang

• Article
  14 February 2024 | Open Access

  Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth

  In Acute Myeloid Leukemia a population of quiescent leukemic stem cells (LSCs) evade chemotherapy and initiate relapse, but what makes them grow again is unknown. Here, the authors show (i) that LSCs hijack ectopic signaling pathways to kick-start their growth and (ii) that growth can be blocked with repurposed drugs in t(8;21) AML sub-type.

  • Sophie G. Kellaway
  • , Sandeep Potluri
  •  & Constanze Bonifer

• Article
  02 January 2024 | Open Access

  Structure-guided design of a selective inhibitor of the methyltransferase KMT9 with cellular activity

  Wang et al. report on an inhibitor of the lysine methyltransferase KMT9 with cellular activity. The inhibitor blocks proliferation of androgen-resistant prostate cancer cells, opening therapeutics avenues to treat this type of cancer.

  • Sheng Wang
  • , Sebastian O. Klein
  •  & Roland Schüle

• Article
  31 October 2023 | Open Access

  A genome-scale metabolic model of parasitic whipworm

  In this work, Bay et al describe the construction of the first genome-scale metabolic model for the parasitic whipworm, Trichuris muris and use it to identify novel metabolic pathways and predict critical enzymes and essential metabolites for worm survival.

  • Ömer F. Bay
  • , Kelly S. Hayes
  •  & Ian S. Roberts

• Article
  08 September 2023 | Open Access

  Activation of the integrated stress response by inhibitors of its kinases

  The integrated stress response (ISR) is the focus of numerous investigations and drug development programs. Here, the authors show that ATP-competitive inhibitors of ISR kinases PERK, PKR and GCN2 inhibit their targets but activate the ISR by directly binding to and activating a sister ISR kinase.

  • Maria Szaruga
  • , Dino A. Janssen
  •  & Anne Bertolotti

• Review Article
  19 August 2023 | Open Access

  Challenges in developing Geroscience trials

  Geroscience is becoming a major hope for preventing age-related diseases and loss of function by targeting biological mechanisms of aging. This article reports a discussion of a research Task Force on the challenges posed by the clinical research in Geroscience so that future gerotherapeutic clinical trials can be conducted successfully.

  • Yves Rolland
  • , Felipe Sierra
  •  & Alex Zhavoronkov

• Article
  18 August 2023 | Open Access

  Lenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation

  Lenalidomide is effective for treating several hematological cancers but has teratogenic effect on the fetus. Here, the authors identify modifications that make lenalidomide more selective and effective when used as a stand-alone molecular glue or integrated in PROTACs.

  • Satoshi Yamanaka
  • , Hirotake Furihata
  •  & Tatsuya Sawasaki

• Article
  19 July 2023 | Open Access

  Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction

  Dynamin-related protein 1 (Drp1) mediates physiological and pathological mitochondrial fission, and the latter can be selectively blocked by a peptide inhibitor. Here, the authors identify a small molecule that mimics the benefits of this peptide inhibitor in cells and a mouse model of endotoxemia.

  • Luis Rios
  • , Suman Pokhrel
  •  & Daria Mochly-Rosen

• Article
  07 July 2023 | Open Access

  Lateral membrane organization as target of an antimicrobial peptidomimetic compound

  The mechanism of action of the antibacterial tripeptide AMC-109 is unclear. Here, Melcrová et al. show that AMC-109 self-assembles into stable aggregates with a cationic surface, and then individual peptides insert into the bacterial membrane and disrupt membrane nanodomains, thus affecting membrane function without forming pores.

  • Adéla Melcrová
  • , Sourav Maity
  •  & Wouter H. Roos

• Article
  06 July 2023 | Open Access

  Induction of lysosomal exocytosis and biogenesis via TRPML1 activation for the treatment of uranium-induced nephrotoxicity

  The roles of lysosomes in uranium (U) decorporation and detoxification remain to be elucidated. Here, the authors demonstrate that TRPML1 activation is an attractive therapeutic strategy to induce lysosomal exocytosis and biogenesis for the treatment of U-induced nephrotoxicity.

  • Dengqin Zhong
  • , Ruiyun Wang
  •  & Honghong Chen

• Article
  06 June 2023 | Open Access

  Durable contraception in the female domestic cat using viral-vectored delivery of a feline anti-Müllerian hormone transgene

  This study demonstrates the safety and long-term efficacy of a single-dose, injectable contraceptive in female domestic cats. Treated females remained contracepted for over two years, and did not ovulate or produce kittens when paired with males.

  • Lindsey M. Vansandt
  • , Marie-Charlotte Meinsohn
  •  & David Pépin

• Article
  02 June 2023 | Open Access

  Therapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD₄-selective WNT surrogate in mice

  The WNT/b-catenin pathway is essential for bloodbrain barrier (BBB) and blood-retina barrier (BRB) function. A bioengineered FZD4-selective WNT surrogate demonstrated systemic efficacy during BRB and ischemic stroke BBB dysfunction in mice.

  • Jie Ding
  • , Sung-Jin Lee
  •  & Calvin J. Kuo

• Article
  29 May 2023 | Open Access

  Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis

  Sui et al. elucidate the mechanisms of action for small molecule inhibitors of human triacylglycerol synthesis enzyme DGAT1 and provide insights into how these inhibitors achieve selectivity for DGAT1 rather than other closely related MBOAT enzymes.

  • Xuewu Sui
  • , Kun Wang
  •  & Tobias C. Walther

• Article
  29 April 2023 | Open Access

  Nanoparticle-mediated TRPV1 channel blockade amplifies cancer thermo-immunotherapy via heat shock factor 1 modulation

  TRPV1 has been associated with proliferation and survival of tumors, and can be activated by heat and other stimuli. Here, the authors block TRPV1 using photothermal nanoparticles encapsulating a TRPV1 antagonist in different cancer types, which can enhance thermo-immunotherapy in pancreatic cancer models.

  • Ting Li
  • , Shuhui Jiang
  •  & Huabing Chen

• Article
  14 February 2023 | Open Access

  On-demand male contraception via acute inhibition of soluble adenylyl cyclase

  Half of all pregnancies are unintended; thus, existing family planning options are inadequate. This proof-of-concept study validates an on-demand contraception strategy for men, showing high effectiveness in quickly and temporarily reducing male fertility in mice.

  • Melanie Balbach
  • , Thomas Rossetti
  •  & Lonny R. Levin

• Article
  11 February 2023 | Open Access

  Small molecule inhibitors of 15-PGDH exploit a physiologic induced-fit closing system

  Inhibition of 15-prostaglandin dehydrogenase (15-PGDH) is a promising therapeutic target for regenerative medicine. We report the structure of 15-PGDH in complex with two different inhibitors. Unexpectedly, access to the binding pocket is regulated by a dynamic “lid” of the enzyme.

  • Wei Huang
  • , Hongyun Li
  •  & Derek J. Taylor

• Comment
  31 January 2023 | Open Access

  A two-faced selectivity solution to target SMARCA2 for cancer therapy

  Two new studies exploring PROTAC-mediated degradation of SMARCA2 for cancer therapy solve an apparently intractable selectivity challenge with SMARCA4 by utilising the requirement for a productive ternary complex between the protein, PROTAC and ligase complex.

  • John D. Harling
  •  & Christopher P. Tinworth

• Article
  26 December 2022 | Open Access

  Pharmacological inhibition of Lin28 promotes ketogenesis and restores lipid homeostasis in models of non-alcoholic fatty liver disease

  The Lin28/let-7 axis regulates metabolic pathways in normal and pathological contexts. Here the authors show that pharmacological inhibition of Lin28 protects against lipid accumulation in multiple preclinical models of nonalcoholic fatty liver disease.

  • Evangelia Lekka
  • , Aleksandra Kokanovic
  •  & Jonathan Hall

• Article
  21 November 2022 | Open Access

  Structural basis of synthetic agonist activation of the nuclear receptor REV-ERB

  The nuclear receptor REV-ERBα is a receptor for heme and plays a role in a range of physiological processes. Here, the authors provide the first structure of REV-ERB bound to a synthetic nonporphyrin ligand defining key mechanistic differences to how heme binds.

  • Meghan H. Murray
  • , Aurore Cecile Valfort
  •  & Thomas P. Burris

• Article
  09 November 2022 | Open Access

  Structural dynamics of AAA + ATPase Drg1 and mechanism of benzo-diazaborine inhibition

  Drg1 is a cytoplasmic AAA + ATPase responsible for releasing Rlp24 during ribosome assembly. Here, the authors show that Drg1 structurally and functionally shares many regulatory features with that of Cdc48/p97, suggesting a unfoldase role for Drg1.

  • Chengying Ma
  • , Damu Wu
  •  & Ning Gao

• Article
  10 October 2022 | Open Access

  Structural basis for specific inhibition of the deubiquitinase UCHL1

  The deubiquitinase UCHL1 has been linked to cancer invasiveness and neurodegeneration yet its molecular roles have remained poorly defined. Here the authors reveal the structural basis for how UCHL1 can be specifically inhibited and how chemogenomic probes can be used to dissect its functions in living cells.

  • Christian Grethe
  • , Mirko Schmidt
  •  & Malte Gersch

• Article
  20 September 2022 | Open Access

  Systematic profiling of conditional degron tag technologies for target validation studies

  Conditional Degron Tags are a valuable tool to validate and study novel therapeutic targets. Here, the authors compared 5 orthogonal tags across 16 unique proteins and provide a panel of vectors for users to systematically screen the tags with their own protein of interest.

  • Daniel P. Bondeson
  • , Zachary Mullin-Bernstein
  •  & Alessandra Ianari

• Article
  30 August 2022 | Open Access

  Tackling recalcitrant Pseudomonas aeruginosa infections in critical illness via anti-virulence monotherapy

  Pseudomonas aeruginosa infections are increasingly difficult to treat due to the development of antimicrobial resistance. Here, the authors describe the synthesis, characterisation and efficacy of a quorum sensing inhibitor.

  • Vijay K. Singh
  • , Marianna Almpani
  •  & Laurence G. Rahme

• Article
  16 August 2022 | Open Access

  A TrkB agonist prodrug prevents bone loss via inhibiting asparagine endopeptidase and increasing osteoprotegerin

  BDNS and TrkB are involved in bone fracture healing by inhibiting AEP. Here the authors show that a TrkB agonist prodrug can inhibit AEP and promote bone formation in osteoporotic mice.

  • Jing Xiong
  • , Jianming Liao
  •  & Keqiang Ye

• Article
  04 August 2022 | Open Access

  Accurate determination of CRISPR-mediated gene fitness in transplantable tumours

  Gene fitness and essentiality analyses using in vivo cancer models are challenging due to multiple confounders. Here, the authors develop a quantitative approach to study CRISPR-transduced patient-derived xenografts, which they use to analyse in vivo gene fitness in breast cancers and the biological features that influence uncertainty in fitness estimation.

  • Peter Eirew
  • , Ciara O’Flanagan
  •  & Samuel Aparicio

• Article
  18 July 2022 | Open Access

  Selective activation of Gαob by an adenosine A₁ receptor agonist elicits analgesia without cardiorespiratory depression

  Wall et al. describe the selective activation of an adenosine A1 receptor-mediated intracellular pathway that provides potent analgesia in the absence of sedation or cardiorespiratory depression, paving the way for novel medicines based on the far-reaching concept of selective Gα agonism.

  • Mark J. Wall
  • , Emily Hill
  •  & Bruno G. Frenguelli

• Article
  19 April 2022 | Open Access

  Development of NanoLuc-targeting protein degraders and a universal reporter system to benchmark tag-targeted degradation platforms

  tag-Targeted Protein Degrader (tTPD) systems are powerful tools for preclinical target validation. Here the authors extend the tTPD platform by developing NanoTACs that degrade NanoLuc tagged substrates and benchmark each tTPD system using an interchangeable tag reporter system.

  • Christoph Grohmann
  • , Charlene M. Magtoto
  •  & Rebecca Feltham

• Article
  19 April 2022 | Open Access

  Distinct resistance mechanisms arise to allosteric vs. ATP-competitive AKT inhibitors

  How resistance to different classes of AKT inhibitors can emerge is unclear. Here, the authors show that resistance to allosteric inhibitors is mainly due to mutation of AKT1 while the ATP competitive resistance is driven by activation of PIM kinases in prostate cancer models.

  • Kristin M. Zimmerman Savill
  • , Brian B. Lee
  •  & Kui Lin

• Article
  23 March 2022 | Open Access

  Inhibition of lung microbiota-derived proapoptotic peptides ameliorates acute exacerbation of pulmonary fibrosis

  Here, the authors show that treatment with a monoclonal neutralizing antibody against the lung microbiota-derived proapoptotic peptide corisin ameliorates acute exacerbation of pulmonary fibrosis and severity of endotoxin-induced acute lung injury in mice.

  • Corina N. D’Alessandro-Gabazza
  • , Taro Yasuma
  •  & Esteban C. Gabazza

• Article
  07 March 2022 | Open Access

  Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer

  Deregulation of the BCL-2 family interactions ensures cancer resistance to apoptosis and is a major challenge to current treatments. Here the authors describe a novel therapeutic strategy to overcome two anti-apoptotic mechanisms for cancer therapy.

  • Andrea Lopez
  • , Denis E. Reyna
  •  & Evripidis Gavathiotis

• Article
  17 February 2022 | Open Access

  TrkB agonist antibody ameliorates fertility deficits in aged and cyclophosphamide-induced premature ovarian failure model mice

  Qin et al. report that an agonistic antibody targeting the BDNF receptor TrkB promotes follicle development and oocyte maturation, and reverse ovarian deficits and infertility in aged and cyclophosphamide-induced premature ovarian failure model mice.

  • Xunsi Qin
  • , Yue Zhao
  •  & Bai Lu

• Article
  10 January 2022 | Open Access

  Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps

  Efflux transporters of the RND family confer resistance to multiple antibiotics in Gram-negative bacteria. Here, the authors identify pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through allosteric inhibition of its primary RND transporter.

  • Coline Plé
  • , Heng-Keat Tam
  •  & Ruben C. Hartkoorn

• Article
  10 January 2022 | Open Access

  A proximity biotinylation-based approach to identify protein-E3 ligase interactions induced by PROTACs and molecular glues

  PROTACs and molecular glues target E3 ubiquitin ligases to substrate proteins. Here, the authors develop a proximity biotinylation-based method to identify drug-induced E3 ligase-substrate interactions, enabling the assessment of the target spectrum of PROTACs and molecular glues in cells.

  • Satoshi Yamanaka
  • , Yuto Horiuchi
  •  & Tatsuya Sawasaki

• Article
  15 December 2021 | Open Access

  Small molecule splicing modifiers with systemic HTT-lowering activity

  Here the authors describe the discovery of a class of small molecule splicing modifiers which are orally bioavailable, cross the blood-brain barrier, and lower levels of huntingtin in a mouse model of Huntington’s disease (HD).

  • Anuradha Bhattacharyya
  • , Christopher R. Trotta
  •  & Stuart W. Peltz

• Article
  21 October 2021 | Open Access

  Validation of lipid-related therapeutic targets for coronary heart disease prevention using human genetics

  Drug target Mendelian randomization (MR) uses genetic variation in or near a gene encoding a drug target to anticipate the effect of drug action on the same target. Using drug target MR, the authors prioritized 30 targets that might elicit beneficial effects in the prevention or treatment of coronary heart disease.

  • María Gordillo-Marañón
  • , Magdalena Zwierzyna
  •  & Chris Finan

• Article
  24 September 2021 | Open Access

  Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease

  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
  19 July 2021 | Open Access

  Genetic and chemical inhibition of IRF5 suppresses pre-existing mouse lupus-like disease

  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
  11 May 2021 | Open Access

  Selective inhibition of cullin 3 neddylation through covalent targeting DCN1 protects mice from acetaminophen-induced liver toxicity

  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
  19 March 2021 | Open Access

  Molecular basis of V-ATPase inhibition by bafilomycin A1

  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
  05 March 2021 | Open Access

  Identification of CD318, TSPAN8 and CD66c as target candidates for CAR T cell based immunotherapy of pancreatic adenocarcinoma

  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
  18 February 2021 | Open Access

  Eltrombopag directly inhibits BAX and prevents cell death

  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
  02 February 2021 | Open Access

  Histone Parylation factor 1 contributes to the inhibition of PARP1 by cancer drugs

  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
  12 January 2021 | Open Access

  Structural basis of malaria parasite phenylalanine tRNA-synthetase inhibition by bicyclic azetidines

  Bicyclic azetidine inhibitors are promising antimalarials that target the Plasmodium cytosolic phenylalanine tRNAsynthetase (cFRS). Here, Sharma et al. provide the biochemical and structural basis of its mechanism using co-crystal structure of PvcFRS with BRD1389.

  • Manmohan Sharma
  • , Nipun Malhotra
  •  & Amit Sharma

• Article
  04 January 2021 | Open Access

  Genetic and pharmacological inhibition of the nuclear receptor RORα regulates T_H17 driven inflammatory disorders

  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
  18 September 2020 | Open Access

  Rapid and direct control of target protein levels with VHL-recruiting dTAG molecules

  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
  01 September 2020 | Open Access

  Inhibitors of BRAF dimers using an allosteric site

  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
  26 June 2020 | Open Access

  Genetic drug target validation using Mendelian randomisation

  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
  24 June 2020 | Open Access

  Structural plasticity of SARS-CoV-2 3CL M^pro active site cavity revealed by room temperature X-ray crystallography

  The SARS-CoV-2 3CL main protease (3CL M^pro) 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 M^pro and compare it with the earlier determined low-temperature ligand-free and inhibitor-bound crystal structures.

  • Daniel W. Kneller
  • , Gwyndalyn Phillips
  •  & Andrey Kovalevsky

• Article
  14 May 2020 | Open Access

  Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response

  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