Drug discovery

  • Article
    | Open Access

    The location and extent of intranasal oxytocin brain penetrance has not been shown. Here the authors show that oxytocin, administered intranasally, enters brain regions along the trajectories of the olfactory and trigeminal nerves and there, reaches biologically relevant concentrations.

    • M. R. Lee
    • , T. A. Shnitko
    • , S. W. Blue
    • , A. V. Kaucher
    • , A. J. Winchell
    • , D. W. Erikson
    • , K. A. Grant
    •  & L. Leggio
  • Article
    | Open Access

    Selective C-H trifluoromethoxylation of pyridines remains a formidable synthetic challenge. Here, the authors report a silver-mediated late-stage C-H trifluoromethoxylation of arenes and heteroarenes as limiting reagents with trifluoromethoxide anion.

    • Zhijie Deng
    • , Mingxin Zhao
    • , Feng Wang
    •  & Pingping Tang
  • 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
    • , Shawna Organ
    • , Nozomu Sakai
    • , Fengling Li
    • , Levon Halabelian
    • , Suzanne Ackloo
    • , Amber L. Couzens
    • , Mohammad Eram
    • , David Dilworth
    • , Hideto Fukushi
    • , Rachel Harding
    • , Carlo C. dela Seña
    • , Tsukasa Sugo
    • , Kozo Hayashi
    • , David McLeod
    • , Carlos Zepeda
    • , Ahmed Aman
    • , Maria Sánchez-Osuna
    • , Eric Bonneil
    • , Shinji Takagi
    • , Rima Al-Awar
    • , Mike Tyers
    • , Stephane Richard
    • , Masayuki Takizawa
    • , Anne-Claude Gingras
    • , Cheryl H. Arrowsmith
    • , Masoud Vedadi
    • , Peter J. Brown
    • , Hiroshi Nara
    •  & Dalia Barsyte-Lovejoy
  • 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
    • , Giuseppina La Sala
    • , Sukyo Jeong
    • , Yoo-Kyoung Sohn
    • , Alejandro Panjkovich
    • , Sandrine Georgeon
    • , Tim Kükenshöner
    • , Maria J. Marcaida
    • , Florence Pojer
    • , Marco De Vivo
    • , Dmitri Svergun
    • , Hak-Sung Kim
    • , Matteo Dal Peraro
    •  & Oliver Hantschel
  • Article
    | Open Access

    Codon 158 gain-of-function mutant p53 (158-mutp53) promotes tumourigenesis in lung cancer. Here, the authors show that 158-mutp53 render cancers sensitive to cisplatin and p53 acetylation agents through a mechanism where acetylated mutant p53 upregulates TRAIP and inhibits NF-ĸB signaling.

    • Li Ren Kong
    • , Richard Weijie Ong
    • , Tuan Zea Tan
    • , Nur Afiqah Binte Mohamed Salleh
    • , Matan Thangavelu
    • , Jane Vin Chan
    • , Lie Yong Judice Koh
    • , Giridharan Periyasamy
    • , Jieying Amelia Lau
    • , Thi Bich Uyen Le
    • , Lingzhi Wang
    • , Miyoung Lee
    • , Srinivasaraghavan Kannan
    • , Chandra S. Verma
    • , Chwee Ming Lim
    • , Wee Joo Chng
    • , David P. Lane
    • , Ashok Venkitaraman
    • , Huynh The Hung
    • , Chit Fang Cheok
    •  & Boon Cher Goh
  • Article
    | Open Access

    SARS-CoV-2 uses ACE2 as the entry receptor. Here, the authors show that an ACE2-Ig fusion protein inhibits entry of virus pseudotyped with the SARS-CoV-2 spike protein, show differential binding kinetics of SARS-CoV and SARSCoV-2 spike proteins to ACE2, and determine pharmakocinetic parameters of ACE2-Ig in mice.

    • Changhai Lei
    • , Kewen Qian
    • , Tian Li
    • , Sheng Zhang
    • , Wenyan Fu
    • , Min Ding
    •  & Shi Hu
  • Article
    | Open Access

    Senolytics have the potential to extend healthspan by selectively killing senescent cells (SCs), but senolytics that target Bcl-xl may cause platelet toxicity. Here, the authors generated a Bcl-xl proteolysis-targeting chimera (PROTAC) senolytic, which effectively clears SCs and rejuvenates tissue stem and progenitor cells in naturally aged mice without causing severe thrombocytopenia.

    • Yonghan He
    • , Xuan Zhang
    • , Jianhui Chang
    • , Ha-Neui Kim
    • , Peiyi Zhang
    • , Yingying Wang
    • , Sajid Khan
    • , Xingui Liu
    • , Xin Zhang
    • , Dongwen Lv
    • , Lin Song
    • , Wen Li
    • , Dinesh Thummuri
    • , Yaxia Yuan
    • , Janet S. Wiegand
    • , Yuma T. Ortiz
    • , Vivekananda Budamagunta
    • , Jennifer H. Elisseeff
    • , Judith Campisi
    • , Maria Almeida
    • , Guangrong Zheng
    •  & Daohong Zhou
  • Article
    | Open Access

    Benign prostatic hyperplasia (BPH) is one of the most common diseases affecting aging men with limited therapeutic options. In this study, the authors describe the molecular characterization of BPH performing genomic, transcriptomic and epigenetic analysis of 18 BPH cases.

    • Deli Liu
    • , Jonathan E. Shoag
    • , Daniel Poliak
    • , Ramy S. Goueli
    • , Vaishali Ravikumar
    • , David Redmond
    • , Aram Vosoughi
    • , Jacqueline Fontugne
    • , Heng Pan
    • , Daniel Lee
    • , Domonique Thomas
    • , Keyan Salari
    • , Zongwei Wang
    • , Alessandro Romanel
    • , Alexis Te
    • , Richard Lee
    • , Bilal Chughtai
    • , Aria F. Olumi
    • , Juan Miguel Mosquera
    • , Francesca Demichelis
    • , Olivier Elemento
    • , Mark A. Rubin
    • , Andrea Sboner
    •  & Christopher E. Barbieri
  • Article
    | Open Access

    One potential approach for the treatment of Duchenne muscular dysrophy is to increase expression of the dystrophin homolog utrophin. Here, the authors show that eEF1A2 regulates utrophin expression, and show that 2 FDA-approved drugs upregulate eEIF1A2 and utrophin level in mice, leading to improvement of the dystrophic phenotype.

    • Christine Péladeau
    • , Nadine Adam
    • , Lucas M. Bronicki
    • , Adèle Coriati
    • , Mohamed Thabet
    • , Hasanen Al-Rewashdy
    • , Jason Vanstone
    • , Alan Mears
    • , Jean-Marc Renaud
    • , Martin Holcik
    •  & Bernard J. Jasmin
  • Article
    | Open Access

    Imidazolopiperazines (IZPs) are a class of compounds under clinical development for malaria, but their mechanism of action is unclear. Here, the authors show that IZPs inhibit the parasite’s secretory pathway, affecting protein trafficking and export.

    • Gregory M. LaMonte
    • , Frances Rocamora
    • , Danushka S. Marapana
    • , Nina F. Gnädig
    • , Sabine Ottilie
    • , Madeline R. Luth
    • , Tilla S. Worgall
    • , Gregory M. Goldgof
    • , Roxanne Mohunlal
    • , T. R. Santha Kumar
    • , Jennifer K. Thompson
    • , Edgar Vigil
    • , Jennifer Yang
    • , Dylan Hutson
    • , Trevor Johnson
    • , Jianbo Huang
    • , Roy M. Williams
    • , Bing Yu Zou
    • , Andrea L. Cheung
    • , Prianka Kumar
    • , Timothy J. Egan
    • , Marcus C. S. Lee
    • , Dionicio Siegel
    • , Alan F. Cowman
    • , David A. Fidock
    •  & Elizabeth A. Winzeler
  • 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
    • , Constanze Schanbacher
    • , Sofia Kramer
    • , Martin W. Hümmert
    • , Patricio Godoy
    • , Wolfgang Schmidt-Heck
    • , Peter Nordbeck
    • , Jonas Ludwig
    • , Susanne Homann
    • , Armin Wiegering
    • , Timur Shaykhutdinov
    • , Christoph Kratz
    • , Ruth Knüchel
    • , Hans-Konrad Müller-Hermelink
    • , Andreas Rosenwald
    • , Norbert Frey
    • , Jutta Eichler
    • , Dobromir Dobrev
    • , Ali El-Armouche
    • , Jan G. Hengstler
    • , Oliver J. Müller
    • , Karsten Hinrichs
    • , Friederike Cuello
    • , Alma Zernecke
    •  & 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
    • , Michelle Yee
    • , Priya Ragunathan
    • , Joon Shin
    • , Shashi Bhushan
    • , Junhao Zhu
    • , Tatos Akopian
    • , Olga Kandror
    • , Teck Kwang Lim
    • , Martin Gengenbacher
    • , Qingsong Lin
    • , Eric J. Rubin
    • , Gerhard Grüber
    •  & Thomas Dick
  • Article
    | Open Access

    New fungicides are needed due to emerging resistance shown by crop pathogens. Here, the authors show that a mono-alkyl lipophilic cation protects plants from fungal pathogens by inhibiting fungal mitochondrial respiration, inducing production of reactive oxygen species, triggering fungal apoptosis, and activating innate plant defense.

    • Gero Steinberg
    • , Martin Schuster
    • , Sarah J. Gurr
    • , Tina A. Schrader
    • , Michael Schrader
    • , Mark Wood
    • , Andy Early
    •  & Sreedhar Kilaru
  • Article
    | Open Access

    Nonsense mutations can be corrected by several molecules that activate readthrough of premature termination codon. Here, the authors report that 2,6-diaminopurine efficiently corrects UGA nonsense mutations with no significant toxicity.

    • Carole Trzaska
    • , Séverine Amand
    • , Christine Bailly
    • , Catherine Leroy
    • , Virginie Marchand
    • , Evelyne Duvernois-Berthet
    • , Jean-Michel Saliou
    • , Hana Benhabiles
    • , Elisabeth Werkmeister
    • , Thierry Chassat
    • , Romain Guilbert
    • , David Hannebique
    • , Anthony Mouray
    • , Marie-Christine Copin
    • , Pierre-Arthur Moreau
    • , Eric Adriaenssens
    • , Andreas Kulozik
    • , Eric Westhof
    • , David Tulasne
    • , Yuri Motorin
    • , Sylvie Rebuffat
    •  & Fabrice Lejeune
  • 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
    • , Katharina M. Scherer
    • , Xinliang Liu
    • , Kevin C. Ludwig
    • , Anna Klöckner
    • , Manuel Strach
    • , Hans-Georg Sahl
    • , Ulrich Kubitscheck
    •  & Tanja Schneider
  • Article
    | Open Access

    Hepatocytes grown in a dish are immature and do not metabolize compounds as a real liver would. Here, the authors supply stem cell-derived hepatocytes with amino acids at a higher concentration than nutritionally necessary, changing the metabolism of these cells, making them more mature and useful for drug screening and toxicity studies.

    • Ruben Boon
    • , Manoj Kumar
    • , Tine Tricot
    • , Ilaria Elia
    • , Laura Ordovas
    • , Frank Jacobs
    • , Jennifer One
    • , Jonathan De Smedt
    • , Guy Eelen
    • , Matthew Bird
    • , Philip Roelandt
    • , Ginevra Doglioni
    • , Kim Vriens
    • , Matteo Rossi
    • , Marta Aguirre Vazquez
    • , Thomas Vanwelden
    • , François Chesnais
    • , Adil El Taghdouini
    • , Mustapha Najimi
    • , Etienne Sokal
    • , David Cassiman
    • , Jan Snoeys
    • , Mario Monshouwer
    • , Wei-Shou Hu
    • , Christian Lange
    • , Peter Carmeliet
    • , Sarah-Maria Fendt
    •  & Catherine M. Verfaillie
  • Article
    | Open Access

    Most epigenetic regulator inhibitors target tunnels of active sites, rather than the peptide binding groove, leading to concerns with low selectivity. Here the authors use an amber obligate phage library to rapidly identify isoform-selective inhibitors of SIRT2.

    • Jeffery M. Tharp
    • , J. Trae Hampton
    • , Catrina A. Reed
    • , Andreas Ehnbom
    • , Peng-Hsun Chase Chen
    • , Jared S. Morse
    • , Yadagirri Kurra
    • , Lisa M. Pérez
    • , Shiqing Xu
    •  & Wenshe Ray Liu
  • Article
    | Open Access

    Allelic losses occurring in cancer cells have been suggested as potential targets for therapy. Here, the authors show how recurring loss of heterozygosity of a drug metabolic gene in colorectal cancers can be exploited using a low molecular weight compound.

    • Veronica Rendo
    • , Ivaylo Stoimenov
    • , André Mateus
    • , Elin Sjöberg
    • , Richard Svensson
    • , Anna-Lena Gustavsson
    • , Lars Johansson
    • , Adrian Ng
    • , Casey OʼBrien
    • , Marios Giannakis
    • , Per Artursson
    • , Peter Nygren
    • , Ian Cheong
    •  & Tobias Sjöblom
  • Article
    | Open Access

    Eliminating the need for cleanroom fabrication for thermomechanical characterization of organic samples in a biomedical setting remains a challenge. Here, the authors propose the use of a single drug and collagen particles as resonators, enabling direct measurements on a material during thermal cycling.

    • Peter Ouma Okeyo
    • , Peter Emil Larsen
    • , Eric Ofosu Kissi
    • , Fatemeh Ajalloueian
    • , Thomas Rades
    • , Jukka Rantanen
    •  & Anja Boisen
  • Article
    | Open Access

    Intranasal oxytocin can affect brain function either by direct entry to the brain or by increasing oxytocin levels in blood plasma. Here, the authors show that increases in plasmatic oxytocin account for some but not all of the changes observed following intranasal oxytocin administration.

    • D. A. Martins
    • , N. Mazibuko
    • , F. Zelaya
    • , S. Vasilakopoulou
    • , J. Loveridge
    • , A. Oates
    • , S. Maltezos
    • , M. Mehta
    • , S. Wastling
    • , M. Howard
    • , G. McAlonan
    • , D. Murphy
    • , S. C. R. Williams
    • , A. Fotopoulou
    • , U. Schuschnig
    •  & Y. Paloyelis
  • Article
    | Open Access

    Curli amyloid fibers are important components of bacterial biofilms formed by E. coli and Salmonella. Here, Tursi et al. show that a human monoclonal antibody with pan-amyloid binding activity can disrupt biofilms formed by Salmonella Typhimurium in vitro and in vivo.

    • Sarah A. Tursi
    • , Rama Devudu Puligedda
    • , Paul Szabo
    • , Lauren K. Nicastro
    • , Amanda L. Miller
    • , Connie Qiu
    • , Stefania Gallucci
    • , Norman R. Relkin
    • , Bettina A. Buttaro
    • , Scott K. Dessain
    •  & Çagla Tükel
  • Article
    | Open Access

    CD229 is expressed on the surface of multiple myeloma cells, as well as B and T lymphocytes. Here, the authors engineer CD229-specific CAR T cells and, using patient samples and mouse models, show that treatment with these cells reduces tumour burden and results in limited targeting of T cells.

    • Sabarinath V. Radhakrishnan
    • , Tim Luetkens
    • , Sandra D. Scherer
    • , Patricia Davis
    • , Erica R. Vander Mause
    • , Michael L. Olson
    • , Sara Yousef
    • , Jens Panse
    • , Yasmina Abdiche
    • , K. David Li
    • , Rodney R. Miles
    • , William Matsui
    • , Alana L. Welm
    •  & Djordje Atanackovic
  • Article
    | Open Access

    Cardiovascular calcification is a serious pathology for which effective pharmacological treatments are lacking. Here the authors show that an optimized oligo(ethylene glycol) derivative of inositol phosphate interferes with calcium phosphate crystallization and inhibits soft tissue calcification in vivo following subcutaneous injection.

    • Antonia E. Schantl
    • , Anja Verhulst
    • , Ellen Neven
    • , Geert J. Behets
    • , Patrick C. D’Haese
    • , Marc Maillard
    • , David Mordasini
    • , Olivier Phan
    • , Michel Burnier
    • , Dany Spaggiari
    • , Laurent A. Decosterd
    • , Mark G. MacAskill
    • , Carlos J. Alcaide-Corral
    • , Adriana A. S. Tavares
    • , David E. Newby
    • , Victoria C. Beindl
    • , Roberto Maj
    • , Anne Labarre
    • , Chrismita Hegde
    • , Bastien Castagner
    • , Mattias E. Ivarsson
    •  & Jean-Christophe Leroux
  • Article
    | Open Access

    Neovascular age-related macular degeneration and diabetic retinopathy are currently treated with repeated intravitreous injections of VEGF neutralizing proteins. Here the authors develop a microparticle-loaded tyrosine kinase inhibitor therapy, which is effective for six months after a single injection in preclinical models.

    • Hiroki Tsujinaka
    • , Jie Fu
    • , Jikui Shen
    • , Yun Yu
    • , Zibran Hafiz
    • , Joshua Kays
    • , David McKenzie
    • , Delia Cardona
    • , David Culp
    • , Ward Peterson
    • , Brian C. Gilger
    • , Christopher S. Crean
    • , Jin-Zhong Zhang
    • , Yogita Kanan
    • , Weiling Yu
    • , Jeffrey L. Cleland
    • , Ming Yang
    • , Justin Hanes
    •  & Peter A. Campochiaro
  • Article
    | Open Access

    The cytoplasmic protein FROUNT can bind to chemokine receptors and enhance chemokine signalling. Here, the authors show that inhibiting FROUNT in macrophages either by knockdown of the gene or using the anti-alcoholism drug disulfiram, results in a reduction in tumour growth.

    • Yuya Terashima
    • , Etsuko Toda
    • , Meiji Itakura
    • , Mikiya Otsuji
    • , Sosuke Yoshinaga
    • , Kazuhiro Okumura
    • , Francis H. W. Shand
    • , Yoshihiro Komohara
    • , Mitsuhiro Takeda
    • , Kana Kokubo
    • , Ming-Chen Chen
    • , Sana Yokoi
    • , Hirofumi Rokutan
    • , Yutaka Kofuku
    • , Koji Ohnishi
    • , Miki Ohira
    • , Toshihiko Iizasa
    • , Hirofumi Nakano
    • , Takayoshi Okabe
    • , Hirotatsu Kojima
    • , Akira Shimizu
    • , Shiro Kanegasaki
    • , Ming-Rong Zhang
    • , Ichio Shimada
    • , Hiroki Nagase
    • , Hiroaki Terasawa
    •  & Kouji Matsushima
  • Article
    | Open Access

    Platinum based drugs like cisplatin are common chemotherapy treatments for cancer. Here, the authors report on the in situ formation of platinum nanoparticles in patients and demonstrated how platinum nanoparticles can be synthesized using patients’ blood and provide effective drug delivery and cancer treatments.

    • Xin Zeng
    • , Jie Sun
    • , Suping Li
    • , Jiyun Shi
    • , Han Gao
    • , Wei Sun Leong
    • , Yiqi Wu
    • , Minghui Li
    • , Chengxin Liu
    • , Ping Li
    • , Jing Kong
    • , Yi-Zhou Wu
    • , Guangjun Nie
    • , Yuming Fu
    •  & Gen Zhang
  • 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
    • , Christopher M. Rose
    • , Donald S. Kirkpatrick
    • , Kebing Yu
    •  & Robert A. Blake
  • Article
    | Open Access

    Current inhibitors of platelet integrin αIIbβ3 cause excessive bleeding, which limited their clinical use in cardiac patients. Here the authors design pure orthosteric αIIbβ3 inhibitors that prevent platelet aggregation and thrombosis without causing bleeding in humanized mouse models of thrombosis

    • Brian D. Adair
    • , José L. Alonso
    • , Johannes van Agthoven
    • , Vincent Hayes
    • , Hyun Sook Ahn
    • , I-Shing Yu
    • , Shu-Wha Lin
    • , Jian-Ping Xiong
    • , Mortimer Poncz
    •  & M. Amin Arnaout
  • 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
    • , Lisa M. Perez
    • , Wanliang Shi
    • , Ying Zhang
    •  & James C. Sacchettini
  • Article
    | Open Access

    Counterfeit medicines are a threat to patient health and public safety. Here, the authors use random patterns formed by fluorescent silk microparticles with various excitation and emission pairs as an edible physical unclonable function that can directly be attached onto the surface of medicines.

    • Jung Woo Leem
    • , Min Seok Kim
    • , Seung Ho Choi
    • , Seong-Ryul Kim
    • , Seong-Wan Kim
    • , Young Min Song
    • , Robert J. Young
    •  & Young L. Kim
  • Article
    | Open Access

    Cystine-knot miniprotein are small, highly stable, disulfide-rich peptides with increasing potential as drugs and tumor imaging agents. Here the authors develop cystine-knot miniproteins targeting the vascular tumor marker EDB, and use them as probes for in vivo tumor vasculature imaging.

    • Bonny Gaby Lui
    • , Nadja Salomon
    • , Joycelyn Wüstehube-Lausch
    • , Matin Daneschdar
    • , Hans-Ulrich Schmoldt
    • , Özlem Türeci
    •  & Ugur Sahin
  • Article
    | Open Access

    FXR agonists have been investigated for the treatment of non-alcoholic steatohepatitis and liver fibrosis but the clinical efficacy is not optimal. Here the authors show that enhanced FXR SUMOylation in activated hepatic stellate cells reduces FXR signaling and that this can be rescued by SUMOylation inhibitors.

    • Jiyu Zhou
    • , Shuang Cui
    • , Qingxian He
    • , Yitong Guo
    • , Xiaojie Pan
    • , Pengfei Zhang
    • , Ningning Huang
    • , Chaoliang Ge
    • , Guangji Wang
    • , Frank J. Gonzalez
    • , Hong Wang
    •  & Haiping Hao
  • Article
    | Open Access

    We lack effective treatment for half of children with high-risk neuroblastoma. Here, the authors introduce an algorithm that can predict the effect of interventions on gene expression signatures associated with high disease processes and risk, and identify and validate promising drug targets.

    • Elin Almstedt
    • , Ramy Elgendy
    • , Neda Hekmati
    • , Emil Rosén
    • , Caroline Wärn
    • , Thale Kristin Olsen
    • , Cecilia Dyberg
    • , Milena Doroszko
    • , Ida Larsson
    • , Anders Sundström
    • , Marie Arsenian Henriksson
    • , Sven Påhlman
    • , Daniel Bexell
    • , Michael Vanlandewijck
    • , Per Kogner
    • , Rebecka Jörnsten
    • , Cecilia Krona
    •  & Sven Nelander
  • Article
    | Open Access

    New World arenaviruses utilize the cellular transferrin receptor 1 (TfR1) to enter host cells. Here, the authors develop a TfR1-mimetic immunoadhesin, Arenacept, that targets viral spike complexes and exerts effective pan-reactive neutralization against pathogenic mammarenaviruses.

    • Hadas Cohen-Dvashi
    • , Ron Amon
    • , Krystle N. Agans
    • , Robert W. Cross
    • , Aliza Borenstein-Katz
    • , Mathieu Mateo
    • , Sylvain Baize
    • , Vered Padler-Karavani
    • , Thomas W. Geisbert
    •  & Ron Diskin
  • Article
    | Open Access

    High quality hit identification remains a considerable challenge in de novo drug design. Here, the authors train a generative adversarial network with transcriptome profiles induced by a large set of compounds, enabling it to design molecules that are likely to induce desired expression profiles.

    • Oscar Méndez-Lucio
    • , Benoit Baillif
    • , Djork-Arné Clevert
    • , David Rouquié
    •  & Joerg Wichard
  • Article
    | Open Access

    While biologics have been successfully applied in TNF antagonist treatments, there are no clinically approved small molecules that target TNF. Here, the authors discover potent small molecule inhibitors of TNF, elucidate their molecular mechanism, and demonstrate TNF inhibition in vitro and in vivo.

    • James O’Connell
    • , John Porter
    • , Boris Kroeplien
    • , Tim Norman
    • , Stephen Rapecki
    • , Rachel Davis
    • , David McMillan
    • , Tracy Arakaki
    • , Alex Burgin
    • , David Fox III
    • , Tom Ceska
    • , Fabien Lecomte
    • , Alison Maloney
    • , Alex Vugler
    • , Bruce Carrington
    • , Benjamin P Cossins
    • , Tim Bourne
    •  & Alastair Lawson
  • Article
    | Open Access

    PRDM9 is a PR domain containing histone methyl transferase which expression is normally restricted to the germline that has also been linked to a number of somatic cancers. Here the authors describe the identification of a small molecule that selectivity inhibits the methyltransferase activity of PRDM9 in biochemical and cellular assays

    • Abdellah Allali-Hassani
    • , Magdalena M. Szewczyk
    • , Danton Ivanochko
    • , Shawna L. Organ
    • , Jabez Bok
    • , Jessica Sook Yuin Ho
    • , Florence P. H. Gay
    • , Fengling Li
    • , Levi Blazer
    • , Mohammad S. Eram
    • , Levon Halabelian
    • , David Dilworth
    • , Genna M. Luciani
    • , Evelyne Lima-Fernandes
    • , Qin Wu
    • , Peter Loppnau
    • , Nathan Palmer
    • , S. Zakiah A. Talib
    • , Peter J. Brown
    • , Matthieu Schapira
    • , Philipp Kaldis
    • , Ronan C. O’Hagan
    • , Ernesto Guccione
    • , Dalia Barsyte-Lovejoy
    • , Cheryl H. Arrowsmith
    • , John M. Sanders
    • , Solomon D. Kattar
    • , D. Jonathan Bennett
    • , Benjamin Nicholson
    •  & Masoud Vedadi
  • Article
    | Open Access

    Anticancer drugs often have widespread effects on the cellular proteome. Here, the authors generate a proteome signature library of drug-treated cancer cell lines and develop a software tool to deconvolute drug targets and gain insights into their mechanisms of action.

    • Amir Ata Saei
    • , Christian Michel Beusch
    • , Alexey Chernobrovkin
    • , Pierre Sabatier
    • , Bo Zhang
    • , Ülkü Güler Tokat
    • , Eleni Stergiou
    • , Massimiliano Gaetani
    • , Ákos Végvári
    •  & Roman A. Zubarev
  • Article
    | Open Access

    Cancer stem cells contribute to breast cancer metastasis and recurrence. Here the authors show that TRIB3 enhances breast cancer stemness through interaction with AKT to promote FOXO1 stability, which then increases SOX2 activity.

    • Jin-mei Yu
    • , Wei Sun
    • , Zhen-he Wang
    • , Xiao Liang
    • , Fang Hua
    • , Ke Li
    • , Xiao-xi Lv
    • , Xiao-wei Zhang
    • , Yu-ying Liu
    • , Jiao-jiao Yu
    • , Shan-shan Liu
    • , Shuang Shang
    • , Feng Wang
    • , Zhao-na Yang
    • , Chen-xi Zhao
    • , Xue-ying Hou
    • , Ping-ping Li
    • , Bo Huang
    • , Bing Cui
    •  & Zhuo-Wei Hu
  • Article
    | Open Access

    PARG catalyzes the removal of poly(ADP-ribose) (PAR) from target proteins and executes critical functions in the DNA damage response. Here the authors provide structural and biological insight with small molecule PARG inhibitors and show that PARG inhibition sensitizes cells to ionizing radiation and kills cancer cells through replication fork defects.

    • Jerry H. Houl
    • , Zu Ye
    • , Chris A. Brosey
    • , Lakshitha P. F. Balapiti-Modarage
    • , Sarita Namjoshi
    • , Albino Bacolla
    • , Daniel Laverty
    • , Brian L. Walker
    • , Yasin Pourfarjam
    • , Leslie S. Warden
    • , Naga Babu Chinnam
    • , Davide Moiani
    • , Roderick A. Stegeman
    • , Mei-Kuang Chen
    • , Mien-Chie Hung
    • , Zachary D. Nagel
    • , Tom Ellenberger
    • , In-Kwon Kim
    • , Darin E. Jones
    • , Zamal Ahmed
    •  & John A. Tainer
  • 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
    • , Gustavo D. Campagnaro
    • , Gabriela Schumann
    • , Louis Maes
    • , Isabel Roditi
    • , Anders Hofer
    • , Harry P. de Koning
    • , Guy Caljon
    •  & Serge Van Calenbergh
  • Article
    | Open Access

    Many cancer cells have increased glucose consumption compared to normal cells, a feature that can be exploited therapeutically. Here, the authors carry out a chemical screen and identify compounds that selectively blocks glucose metabolism in non-small-cell lung cancer cell lines.

    • Chiara Ghezzi
    • , Alicia Wong
    • , Bao Ying Chen
    • , Bernard Ribalet
    • , Robert Damoiseaux
    •  & Peter M. Clark
  • Article
    | Open Access

    Myeloid-derived growth factor (MYDGF) is an angiogenic growth factor with therapeutic potential for ischemic tissue repair and the receptor is still unknown. Here the authors present the crystal structure of human MYDGF and identify its functional epitope through mutagenesis studies.

    • Rebecca Ebenhoch
    • , Abbas Akhdar
    • , Marc R. Reboll
    • , Mortimer Korf-Klingebiel
    • , Priyanka Gupta
    • , Julie Armstrong
    • , Yining Huang
    • , Lee Frego
    • , Irina Rybina
    • , John Miglietta
    • , Anton Pekcec
    • , Kai C. Wollert
    •  & Herbert Nar
  • 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
    • , Joanna Koh
    • , Samantha Lim
    •  & Cheng-I Wang
  • 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
    • , Linda Huang
    • , Kaitlyn Gayvert
    • , Giuseppe Galletti
    • , Martin Stogniew
    • , Joshua E. Allen
    • , Paraskevi Giannakakou
    •  & Olivier Elemento
  • Article
    | Open Access

    Hutchinson–Gilford progeria syndrome causes premature aging. Here the authors show that activation of the DNA damage response at dysfunctional telomeres and transcription of telomeric non-coding RNAs contributes to the pathogenesis, which can be ameliorated by treatment with sequence-specific telomeric antisense oligonucleotides.

    • Julio Aguado
    • , Agustin Sola-Carvajal
    • , Valeria Cancila
    • , Gwladys Revêchon
    • , Peh Fern Ong
    • , Corey Winston Jones-Weinert
    • , Emelie Wallén Arzt
    • , Giovanna Lattanzi
    • , Oliver Dreesen
    • , Claudio Tripodo
    • , Francesca Rossiello
    • , Maria Eriksson
    •  & Fabrizio d’Adda di Fagagna
  • Article
    | Open Access

    Metabolic reprogramming is a hallmark of pancreatic ductal adenocarcinoma (PDA). Here, the authors show that in PDA cells redox and central carbon metabolism are driven by an eIF4F dependent translation program, and combined targeting of eIF4A and glutaminase can impact PDA proliferation.

    • Karina Chan
    • , Francis Robert
    • , Christian Oertlin
    • , Dana Kapeller-Libermann
    • , Daina Avizonis
    • , Johana Gutierrez
    • , Abram Handly-Santana
    • , Mikhail Doubrovin
    • , Julia Park
    • , Christina Schoepfer
    • , Brandon Da Silva
    • , Melissa Yao
    • , Faith Gorton
    • , Junwei Shi
    • , Craig J. Thomas
    • , Lauren E. Brown
    • , John A. Porco Jr.
    • , Michael Pollak
    • , Ola Larsson
    • , Jerry Pelletier
    •  & Iok In Christine Chio
  • Article
    | Open Access

    The Aza Paternò-Büchi reaction is arguably among the most direct approaches to functionalized azetidines, which are common medicinal scaffolds. Here, the authors report a mild and selective visible light-enabled intramolecular aza Paternò-Büchi reaction yielding bicyclic azetidines in high yields and diastereoselectivity.

    • Marc R. Becker
    • , Alistair D. Richardson
    •  & Corinna S. Schindler
  • Article
    | Open Access

    DNA-dependent protein kinase (DNA-PK) plays a major role in the DNA damage response upon double-strand break formation. Here, the authors show that the DNA-PK inhibitor AZD7648, enhances the activity of radiotherapy, chemotherapy and the PARP inhibitor olaparib in multiple mouse tumour models.

    • Jacqueline H. L. Fok
    • , Antonio Ramos-Montoya
    • , Mercedes Vazquez-Chantada
    • , Paul W. G. Wijnhoven
    • , Valeria Follia
    • , Neil James
    • , Paul M. Farrington
    • , Ankur Karmokar
    • , Sophie E. Willis
    • , Jonathan Cairns
    • , Jenni Nikkilä
    • , David Beattie
    • , Gillian M. Lamont
    • , M. Raymond V. Finlay
    • , Joanne Wilson
    • , Aaron Smith
    • , Lenka Oplustil O’Connor
    • , Stephanie Ling
    • , Stephen E. Fawell
    • , Mark J. O’Connor
    • , Simon J. Hollingsworth
    • , Emma Dean
    • , Frederick W. Goldberg
    • , Barry R. Davies
    •  & Elaine B. Cadogan