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Article
| Open Access
De novo generation of multi-target compounds using deep generative chemistry
Polypharmacology drugs are compounds designed to inhibit multiple protein targets. Here, authors use recent advances in AI to rapidly generate polypharmacology compounds against any pair of protein targets, experimentally validating numerous compounds targeting MEK1 and mTOR.
- Brenton P. Munson
- , Michael Chen
- & Trey Ideker
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Article
| Open Access
A vascularized breast cancer spheroid platform for the ranked evaluation of tumor microenvironment-targeted drugs by light sheet fluorescence microscopy
Assessing tumour microenvironment-targeted drug candidates remains challenging. Here, the authors develop a comprehensive screening platform that allows for monitoring, quantifying, and ranking drug-induced effects in self-organizing, vascularized tumour spheroids.
- David Ascheid
- , Magdalena Baumann
- & Erik Henke
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Article
| Open Access
Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition
The differential effects of targeting individual domains of multidomain enzymatic proteins are generally poorly understood. Here, the authors demonstrate lineage-specific sensitivities to domain-specific inhibition of EP300/CBP proteins across cancer and link these effects in group 3 medulloblastoma to control of a transcriptional dependency network.
- Noha A. M. Shendy
- , Melissa Bikowitz
- & Adam D. Durbin
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Article
| Open Access
The physiological interactome of TCR-like antibody therapeutics in human tissues
The use of bispecific antibodies to target tumour-specific epitopes presented by MHC molecules in tumour tissue is a promising avenue for cancer immunotherapy. Here the authors use a mass-spectrometry guided analysis to identify off-target MHC-peptide complexes that bind to TCR-like antibodies next to the target peptide, enabling a novel approach to monitoring of antibody specificity during clinical maturation and development.
- Estelle Marrer-Berger
- , Annalisa Nicastri
- & Nicola Ternette
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Article
| Open Access
Nanoparticles targeting mutant p53 overcome chemoresistance and tumor recurrence in non-small cell lung cancer
In non-small cell lung cancer (NSCLC), inactivating p53 mutations can drive resistance to cisplatin. Here, the authors develop fluplatin nanoparticles comprising a prodrug of cisplatin and fluvastin (mutant p53 inhibitor) which selectively degrades mutant p53, prevent tumor recurrences in preclinical models of p53 mutant NSCLC.
- Yu-Yang Bi
- , Qiu Chen
- & Hu-Lin Jiang
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Article
| Open Access
Delivery of a BET protein degrader via a CEACAM6-targeted antibody–drug conjugate inhibits tumour growth in pancreatic cancer models
Therapeutic options for pancreatic ductal adenocarcinoma (PDAC) are limited. Here the authors report the characterization of a CEACAM6-targeting antibody drug conjugate loaded with a BET protein degrader, showing antitumour activity in PDAC preclinical models.
- Youya Nakazawa
- , Masayuki Miyano
- & Akihito Machinaga
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Article
| Open Access
Targeting P2Y14R protects against necroptosis of intestinal epithelial cells through PKA/CREB/RIPK1 axis in ulcerative colitis
P2Y14R regulates necroptosis of intestinal epithelial cells though PKA/CREB/RIPK1 axis in the pathogenesis of ulcerative colitis (UC). Targeting P2Y14R with a small molecule inhibitor improves dextran sulfate sodium-induced UC in mice, suggesting P2Y14R as a promising target for treatment of UC.
- Chunxiao Liu
- , Hui Wang
- & Qinghua Hu
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Article
| Open Access
MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation
Several molecular mechanisms, including retinoblastoma protein RB1 deficiency, explain CDK4/6 inhibitors resistance in cancer. Here, the authors show that MYC amplification induces CDK4/6 inhibitors resistance through transcriptional regulation of KLHL42, leading to RB1 degradation and targeting MYC overcomes CDK4/6 resistance in preclinical cancer models.
- Jian Ma
- , Lei Li
- & Lei Li
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Article
| Open Access
Structure of the p53 degradation complex from HPV16
HPV’s E6 protein promotes cancer by degrading p53. This study reveals the cryoEM structure of HPV16 E6 in complex with E6AP and p53, highlighting their picomolar affinity and large protein-protein interaction interface.
- John C. K. Wang
- , Hannah T. Baddock
- & Aaron H. Nile
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Article
| Open Access
KDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma
There is lack of therapies targeting the PAX3-FOXO1 fusion oncogene in fusion-positive rhabdomyosarcoma (FP-RMS). Here, the authors identify and characterise an inhibitor with highest inhibition of histone lysine demethylase 3B that suppresses PAX3-FOXO1 activity in FP-RMS.
- Yong Yean Kim
- , Berkley E. Gryder
- & Javed Khan
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Article
| Open Access
Randomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk adult outpatients
In this clinical trial, the authors show that a 5-day molnupiravir treatment reduces SARS-CoV-2 viral load in at-risk outpatients by day 5 but mostly fails to clear virus, leads to lower spike antibody response by day 14 and higher virus mutation rates.
- Joseph F. Standing
- , Laura Buggiotti
- & Francis Yongblah
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Article
| Open Access
Ultrasmall metal alloy nanozymes mimicking neutrophil enzymatic cascades for tumor catalytic therapy
Emulating the killing function of neutrophils, which involves the enzymatic cascade of superoxide dismutase (SOD) and myeloperoxidase (MPO), is promising for cancer therapy, but developing SOD-MPO cascade in one nanozyme is challenging. Here the authors report ultrasmall AuPd alloy nanozymes that mimic neutrophil enzymatic cascades for catalytic treatment of tumors.
- Xiangqin Meng
- , Huizhen Fan
- & Kelong Fan
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Article
| Open Access
Durvalumab and guadecitabine in advanced clear cell renal cell carcinoma: results from the phase Ib/II study BTCRC-GU16-043
Preclinical studies have suggested the synergistic effect of epigenetic modulators and immunotherapy. Here the authors report the results of a phase Ib/II trial of durvalumab and guadecitabine in advanced clear cell renal cell carcinoma.
- Yousef Zakharia
- , Eric A. Singer
- & Ajjai Alva
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Article
| Open Access
Identification of a highly conserved neutralizing epitope within the RBD region of diverse SARS-CoV-2 variants
Most recent SARS-CoV-2 variants showed exceptional immune evasion properties. Here, the authors identify a highly conserved epitope within the RBD targeted by a broad spectrum neutralizing antibody BA7535 that shows therapeutic antiviral potency in mouse studies.
- Yanqun Wang
- , An Yan
- & Jincun Zhao
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Article
| Open Access
Discovery of a peripheral 5HT2A antagonist as a clinical candidate for metabolic dysfunction-associated steatohepatitis
Metabolic Dysfunction-Associated Steatohepatitis (MASH), an advanced form of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), can progress to liver fibrosis. Here, the authors develop a peripheral 5HT2A antagonist for the treatment of MASLD and MASH.
- Haushabhau S. Pagire
- , Suvarna H. Pagire
- & Jin Hee Ahn
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Article
| Open Access
Generation and optimization of off-the-shelf immunotherapeutics targeting TCR-Vβ2+ T cell malignancy
Clonal Vb2 usage is common among patients with mature T cell lymphoma. Here the authors report the generation of allogeneic CAR-T cells selectively targeting TCR Vb2+ on malignant T cells, with limited normal T cell destruction.
- Jingjing Ren
- , Xiaofeng Liao
- & Michael Girardi
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Article
| Open Access
The HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results
Antibody drug conjugates (ADCs) with pyrrolobenzodiazepine (PBD) payloads are promising cancer therapeutics but are limited by toxicity. Here, the authors develop a HER2-targeted ADC (DHES0815A) with a reduced potency PBD payload that demonstrated promising preclinical efficacy and nonhuman primate tolerability, but culminated in a phase I clinical trial in patients with metastatic breast cancer which was terminated due to toxicity.
- Gail D. Lewis
- , Guangmin Li
- & Eunpi Cho
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Article
| Open Access
Metallopolymer strategy to explore hypoxic active narrow-bandgap photosensitizers for effective cancer photodynamic therapy
Iridium-based photosensitizers exhibit good photocatalytic performance, but the in vivo applications are hindered by conventional O2-dependent Type-II photochemistry and poor absorption. Here, the authors report a general metallopolymerization strategy for engineering iridium complexes exhibiting Type-I photochemistry and enhancing absorption intensity in the blue to near-infrared region.
- Zhao Zhang
- , Zixiang Wei
- & Xuanjun Zhang
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Article
| Open Access
Pharmaceutical targeting of OTUB2 sensitizes tumors to cytotoxic T cells via degradation of PD-L1
PD-L1 expression on the surface of cancer cells is believed to contribute to tumor immune evasion via triggering the inhibitory T cell co-receptor, PD-1, resulting in decreased T cell cytotoxicity. Here authors show that OTUB2 regulates PD-L1 expression via inhibition of its ubiquitin-mediated degradation, and that OTUB2 inhibition increases T cell cytotoxicity directed against tumors.
- Wenfeng Ren
- , Zilong Xu
- & Ningshao Xia
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Article
| Open Access
A pilot study of alternative substrates in the critically Ill subject using a ketogenic feed
Critical illness leads to altered metabolic states and bioenergetic failure caused by impaired utilisation of glucose, fatty acids and amino acids. Here the authors show ketogenic diets may provide a safe and acceptable alternative metabolic fuel enabling energy production and maintaining tissue homeostasis.
- Angela McNelly
- , Anne Langan
- & Zudin A. Puthucheary
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Article
| Open Access
A phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity
Mazdutide is a once-weekly glucagon-like peptide-1 (GLP-1) and glucagon receptor dual agonist. Here, the authors show mazdutide was well tolerated over 24 weeks and demonstrated significant and clinically meaningful body weight loss, compared with placebo, in Chinese overweight adults or adults with obesity.
- Linong Ji
- , Hongwei Jiang
- & Lei Qian
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Article
| Open Access
Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms
Three drugs initially developed for other conditions, 2,3-dimercapto-1-propanesulfonic acid (DMPS), marimastat and varespladib, have shown promise in preventing the lethality of snakebite envenoming. Here, Hall et al., show that a combination of these drugs can combat the local dermonecrotic effects caused by diverse cytotoxic venoms.
- Steven R. Hall
- , Sean A. Rasmussen
- & Nicholas R. Casewell
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Article
| Open Access
Near-infrared light-triggered prodrug photolysis by one-step energy transfer
Prodrug photolysis enables spatiotemporal control of drug release at the desired lesions, but most of the photocleavable groups cannot be directly activated by near-infrared (NIR) light that features deep penetration and low phototoxicity. Here, the authors report an upconversion-like process via only one step of energy transfer for NIR light-triggered prodrug photolysis.
- Kaiqi Long
- , Wen Lv
- & Weiping Wang
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Article
| Open Access
Explainable machine learning for profiling the immunological synapse and functional characterization of therapeutic antibodies
Therapeutic antibodies are crucial in treating severe diseases. Here, the authors introduce scifAI, an open-source explainable AI framework for analyzing imaging flow cytometry data, enabling rapid screening of therapeutic antibody candidates.
- Sayedali Shetab Boushehri
- , Katharina Essig
- & Fabian Schmich
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Article
| Open Access
A simeprevir-inducible molecular switch for the control of cell and gene therapies
Chemical inducer of dimerization (CID) modules can be used to effectively control biological processes; however, CID modules have been explored primarily in engineering cells for in vitro applications using inducers that have limited clinical utility. Here, the authors identify a CID module with favorable properties to enable rapid translation from in vitro applications to potential use in humans.
- Stacey E. Chin
- , Christina Schindler
- & Natalie J. Tigue
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Article
| Open Access
The Imageable Genome
The impact of genomic discoveries on global health depends on their efficient translation into clinically applicable testing. Here, the authors present the Imageable Genome - the part of the human genome whose expression can be assessed via molecular imaging - to accelerate translation and to bridge the fields of genomics and molecular imaging.
- Pablo Jané
- , Xiaoying Xu
- & Martin A. Walter
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Article
| Open Access
Targeting nucleic acid phase transitions as a mechanism of action for antimicrobial peptides
In this work the authors describe antimicrobial peptides (AMPs)-driven phase transitions of intracellular nucleic acids, whereby AMPs induce compaction and phase separation of nucleic acids, resulting in their sequestration and eventual cell death.
- Tomas Sneideris
- , Nadia A. Erkamp
- & Tuomas P. J. Knowles
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Article
| Open Access
Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer
Cuproptosis regulation in tumors is unclear. Here the authors find that copper promotes METTL16 lactylation, inducing cuproptosis via stabilizing FDX1 in gastric cancer. Targeting lactyl-METTL16 and cuproptosis offers a potential feasible strategy for cancer therapy.
- Lianhui Sun
- , Yuan Zhang
- & Chen Huang
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Article
| Open Access
Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir
In this study, the authors report the structure-based discovery and preclinical evaluation of 2 simnotrelvir, an orally bioavailable 3CLpro inhibitor that blocks replication of SARS-CoV-2 variants in 3 vitro, shows robust efficacy in a mouse model and good safety and pharmacokinetic profiles in rats 4 and monkeys.
- Xiangrui Jiang
- , Haixia Su
- & Yechun Xu
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Article
| Open Access
Dalpiciclib and pyrotinib in women with HER2-positive advanced breast cancer: a single-arm phase II trial
Dalpiciclib is a CDK4/6 inhibitor, recently approved for treatment in advanced breast cancer patients in China. Here, the authors report the results of a phase II trial investigating oral dalpiciclib (CDK4/6 inhibitor) and pyrotinib (pan-HER inhibitor) in patients with HER2-positive metastatic breast cancer.
- Min Yan
- , Limin Niu
- & Huajun Li
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Article
| Open Access
mRNA vaccine quality analysis using RNA sequencing
mRNA vaccines must be rigorously analysed to measure their integrity and detect contaminants, which can be time-consuming and costly. Here, authors describe a method to analyse mRNA vaccine quality using long-read sequencing and a custom bioinformatic pipeline.
- Helen M. Gunter
- , Senel Idrisoglu
- & Tim R. Mercer
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Article
| Open Access
Dual hypoxia-responsive supramolecular complex for cancer target therapy
The natural product BE-43547A2 (BE) could potentially serve as a template of hypoxia target strategy for treating pancreatic cancer, but the unsatisfactory pharmacokinetics profile and severe toxicity impeded the application of BE or its derivatives. Here the authors report a supramolecular dual hypoxia-responsive BE-based complex for achieving efficient drug delivery within tumors.
- Jian-Shuang Guo
- , Juan-Juan Li
- & Yue Chen
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Article
| Open Access
Hyodeoxycholic acid ameliorates nonalcoholic fatty liver disease by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling
Nonalcoholic fatty liver disease (NAFLD) is often linked to disrupted bile acid homeostasis. Here, the authors show hyodeoxycholic acid (HDCA) ameliorates nonalcoholic fatty liver disease by inhibiting the formation of RAN/CRM1/PPARα nuclear export heterotrimer, resulting in increased nuclear localization of PPARα and activated fatty acid oxidation.
- Jing Zhong
- , Xiaofang He
- & Houkai Li
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Article
| Open Access
Propensity of selecting mutant parasites for the antimalarial drug cabamiquine
Authors utilize a number of models (mathematical, in vitro and in vivo infection) to analyse pre-clinical and Phase I clinical trial data, in regard to potential risk of resistance associated with a Plasmodium falciparum inhibitor, cabamiquine.
- Eva Stadler
- , Mohamed Maiga
- & Thomas Spangenberg
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Review Article
| Open AccessChallenges 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
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Article
| Open Access
A genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiology
The authors identify genetic variation associated with properties of the internal biological structures of blood cells in hundreds of genes and show how such discoveries can be used to improve understanding of cellular mechanisms causing disease.
- Parsa Akbari
- , Dragana Vuckovic
- & William J. Astle
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Article
| Open Access
Combining gut microbiota modulation and chemotherapy by capecitabine-loaded prebiotic nanoparticle improves colorectal cancer therapy
Gut microbiota regulates colorectal cancer (CRC) progression and respond to therapy. Here the authors generate nanoparticles using prebiotic micelles and loaded with the chemo drug capecitabine that boost gastrointestinal probiotic response, increase anti-tumour immunity and improve survival when provided orally in CRC preclinical murine models.
- Tianqun Lang
- , Runqi Zhu
- & Yaping Li
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Article
| Open Access
Chemically programmed STING-activating nano-liposomal vesicles improve anticancer immunity
Agonists of the cytosolic DNA-sensing STING pathway potently remodel the tumour immune microenvironment to support anti-tumour adaptive immunity, but at the expense of adverse systemic inflammation. Here authors exchange the STING agonist MSA-2 with its prodrugs that are suitable for nano-liposomal delivery and thus achieve increased efficiency and decreased toxicity.
- Xiaona Chen
- , Fanchao Meng
- & Hangxiang Wang
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Article
| Open Access
Cancer cell-mitochondria hybrid membrane coated Gboxin loaded nanomedicines for glioblastoma treatment
Gboxin, an inhibitor of oxidative phosphorylation (OXPHOS), can suppress the proliferation of glioblastoma (GBM) cells. Here the authors describe the design of a cancer cell-mitochondria hybrid membrane camouflaged reactive oxygen species (ROS)-responsive nanoparticle loaded with Gboxin, showing anti-tumor responses in GBM preclinical models.
- Yan Zou
- , Yajing Sun
- & Bingyang Shi
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Article
| Open Access
Macrocyclization of linear molecules by deep learning to facilitate macrocyclic drug candidates discovery
Macrocyclization of bioactive acyclic molecules provides a potential avenue to yield novel chemical scaffolds with improved pharmacological properties. Here, the authors propose a deep learning based macrocyclization method to generate diverse macrocycles from a given acyclic molecule.
- Yanyan Diao
- , Dandan Liu
- & Honglin Li
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Article
| Open Access
Dose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib
Pre-clinical studies have demonstrated the anti-tumor activity of selective inhibitors of CDK7, including samuraciclib. Here the authors report the results from dose escalation and two expansion cohorts in patients with breast cancer of a multi-modular Phase I clinical trial of samuraciclib as anti-cancer treatment.
- R. C. Coombes
- , Sacha Howell
- & Matthew G. Krebs
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Article
| Open Access
An optimized Nurr1 agonist provides disease-modifying effects in Parkinson’s disease models
An optimized agonist of Nurr1, 4A7C-301, protects dopamine neurons against environmental and genetic risk factors of Parkinson’s disease (PD) in vitro, and improves both motor and non-motor deficits in male rodent models of PD.
- Woori Kim
- , Mohit Tripathi
- & Kwang-Soo Kim
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Article
| Open Access
Safety and immunogenicity of a tetravalent and bivalent SARS-CoV-2 protein booster vaccine in men
Here the authors present interim results from a clinical trial of a protein-based tetravalent SARS-CoV-2 vaccine (SCTV01E). SCTV01E demonstrates a comparable safety profile to a bivalent protein vaccine, while exhibiting superior immunogenicity compared to both a bivalent protein vaccine and an mRNA vaccine.
- Suad Hannawi
- , Linda Saf Eldin
- & Liangzhi Xie
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Article
| 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
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Article
| Open Access
From a drug repositioning to a structure-based drug design approach to tackle acute lymphoblastic leukemia
Deoxycytidine kinase is the rate-limiting enzyme of the salvage pathway and it has recently emerged as a target for antiproliferative therapies for cancers where it is essential. Here, the authors develop a potent inhibitor applying an iterative multidisciplinary approach, which relies on computational design coupled with experimental evaluations.
- Magali Saez-Ayala
- , Laurent Hoffer
- & Xavier Morelli
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Article
| Open Access
Identification of indocyanine green as a STT3B inhibitor against mushroom α-amanitin cytotoxicity
There is currently no specific antidote for death cap mushroom poisoning treatment. Here, the authors identify STT3B as a druggable target and show that indocyanine green is a STT3B inhibitor that can block α-amanitin toxicity in cell lines, liver organoids and mice.
- Bei Wang
- , Arabella H. Wan
- & Qiao-Ping Wang
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Article
| Open Access
Automated optimisation of solubility and conformational stability of antibodies and proteins
Antibodies find key applications in research, diagnostics, and therapeutics, but their development can be impeded by poor stability or solubility. Here the authors developed a computational strategy that enables antibody optimisation, without affecting functionality.
- Angelo Rosace
- , Anja Bennett
- & Pietro Sormanni
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Article
| Open Access
Neuraminidase 1 promotes renal fibrosis development in male mice
The influenza virus neuraminidase has been well documented, yet the functions of mammalian neuraminidases remain less explored. Here, the authors show that neuraminidase 1 promotes renal fibrosis development by interacting with ALK5 to activate SMAD2/3.
- Qian-Qian Chen
- , Kang Liu
- & Lei Zhang
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Article
| Open Access
Continuous Spatiotemporal Therapy of A Full-API Nanodrug via Multi-Step Tandem Endogenous Biosynthesis
Nanomedicine is important in cancer therapy, but loading, drug release, and therapeutic effectiveness issues limit the translation to the clinic. Here, authors report a full-API nanodrug with an ideal API content and pH-responsive release for continuous spatiotemporal cancer therapy based on PpIX-heme-CO/Fe2+/BV-BR metabolic pathway.
- Fang Fang
- , Sa Wang
- & Jinfeng Zhang
The pan-PPAR agonist lanifibranor improves cardiometabolic health in patients with metabolic dysfunction-associated steatohepatitis