ArticleCell2024
First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure.
Open access · bronzeAbstract readClinical Trial, Phase I
In one paragraph
Article in Cell, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
0numbers the graph read from it
0cells of the map it votes in
38citing papers in PubMed
19.6field-weighted citation impact, top 1% of its field
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
38 citing papers in PubMed, 53 citations in OpenAlex.
- Mitogen-activated protein kinase kinase 4 (MKK4) as a promising therapeutic target in liver diseases: a review.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- Solute Carrier Family 1 Member 5 (SLC1A5)-dependent glutamine transport regulates macrophage senescence and efferocytosis during liver regeneration.Molecular biomedicine · 2026Article
- The anion channel GPR89 is a tumor-specific dependency in breast cancer.Nature communications · 2026Article
- How Physiology and Pharmacology Shape Liver Regeneration: From Molecules and Cells to Trials.International journal of molecular sciences · 2026Review
- Chlorogenic acid promotes liver regeneration after partial hepatectomy through activating Nrf2 via directly targeting Keap1.Acta pharmacologica Sinica · 2026Article
- Proteolytic EphA2 fragments cooperatively promote hepatocellular carcinoma progression.Cell death & disease · 2026Article
- Dual targeted gene delivery strategy mediated by GalNAc-modified lipid nanoparticles enhances liver regeneration through specific knockdown of MKK4.Materials today. Bio · 2026Article
- Darizmetinib (HRX215): A Promising 1st-in-Class Liver Regenerating Drug in Phase 1b/2a Clinical Development, Targeting the Stress Signaling Protein Kinase MKK4.Journal of medicinal chemistry · 2026Article
- Developing a Clinically Practical Biomaterial Platform for Endogenous Liver Regeneration.Gels (Basel, Switzerland) · 2026Review
- Acute-on-chronic liver failure: From definition to pathogenesis and therapy.Chinese medical journal · 2026Review
- Article
- Targeting the JNK Gatekeepers: Structural Evolution and Medicinal Chemistry of MKK4 and MKK7 Inhibitors.Molecules (Basel, Switzerland) · 2026Review
- Nanoemulsion based on natural components enables oral liver-targeting delivery of Schizandrol B to enhance liver regeneration after hepatectomy in hepatocellular carcinoma.Regenerative biomaterials · 2026Article
- Liver regeneration: unraveling the molecular mechanisms and clinical application.Journal of translational medicine · 2025Review
- Global research trends in liver regeneration and immunomodulation: A perspective from bibliometric analysis.Human vaccines & immunotherapeutics · 2025Article
- Liver hypertrophy techniques: a position paper from the Italian Group of Regenerative and Occlusive Worldwide-used techniques of hepatic Hypertrophy (I GROWtoH).Updates in surgery · 2025Article
- Actual perspectives on LDLT in Europe.Updates in surgery · 2025Article
- AIM2-PANoptosome-driven PANoptosis in hepatic lipid dysregulation induced by β-HCH and nanoplastics co-exposure.Apoptosis : an international journal on programmed cell death · 2025Article
- High-Quality In Vivo Chemical Probes for Protein Kinases Disclosed in 2024.ACS pharmacology & translational science · 2025Review
- Discovery of the First Highly Selective 1,4-dihydropyrido[3,4-Journal of medicinal chemistry · 2025Article
Corrections and comments
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Authors and funding
43 authors at 10 institutions in 4 countries.
Stefan ZwirnerDepartment of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, Tübingen 72076, Germany; HepaRegeniX GmbH, Tübingen 72072, Germany.
Anan A Abu RmilahWilliam J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA.
Sabrina KlotzDepartment of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, Tübingen 72076, Germany.
Bent PfaffenrothDepartment of Pharmaceutical Chemistry, University of Tübingen, Tübingen 72076, Germany.
Philip KloevekornDepartment of Pharmaceutical Chemistry, University of Tübingen, Tübingen 72076, Germany.
Athina A MoschopoulouDepartment of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, Tübingen 72076, Germany.
Svenja SchuetteDepartment of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, Tübingen 72076, Germany.
Mathias HaagDr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart 70376, Germany.
Roland SeligHepaRegeniX GmbH, Tübingen 72072, Germany; Department of Pharmaceutical Chemistry, University of Tübingen, Tübingen 72076, Germany.
Kewei LiWilliam J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA.
Wei ZhouWilliam J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA.
Erek NelsonWilliam J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA.
Antti PosoDepartment of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, Tübingen 72076, Germany; School of Pharmacy, University of Eastern Finland, Kuopio 70211, Finland; iFIT Cluster of Excellence (EXC 2180) "Image-guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen 72076, Germany.
Harvey ChenWilliam J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA.
Bruce AmiotWilliam J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA.
Yao JiaWilliam J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA.
Anna MinshewWilliam J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA.
Gregory MichalakWilliam J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA.
Wei CuiDepartment of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, Tübingen 72076, Germany.
Elke RistDepartment of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, Tübingen 72076, Germany.
Thomas LongerichInstitute of Pathology, University Hospital Heidelberg, Heidelberg 69120, Germany.
Birgit JungHepaRegeniX GmbH, Tübingen 72072, Germany.
Philipp FelgendreffWilliam J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA.
Omelyan TrompakDepartment of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, Tübingen 72076, Germany.
Prem K PremsrirutMirimus Inc, 760 Parkside Ave, Brooklyn, NY 11226, USA.
Katharina GriesDepartment of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, Tübingen 72076, Germany.
Thomas E MuerdterDr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart 70376, Germany.
Georg HeinkeleDr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart 70376, Germany.
Torsten WuestefeldLaboratory for In Vivo Genetics & Gene Therapy, Genome Institute of Singapore, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138672, Singapore; School of Biological Sciences, Nanyang Technological University of Singapore, Singapore 637551, Singapore.
David ShapiroHepaRegeniX GmbH, Tübingen 72072, Germany.
Markus WeissbachHepaRegeniX GmbH, Tübingen 72072, Germany.
Alfred KoenigsraineriFIT Cluster of Excellence (EXC 2180) "Image-guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen 72076, Germany; German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Department of General-, Visceral, and Transplant Surgery, University Hospital Tübingen, Tübingen 72076, Germany.
Bence SiposDepartment of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, Tübingen 72076, Germany.
Eiso AbZoBio B.V., Leiden 2333 CH, the Netherlands.
Magdalena Ortiz ZacariasZoBio B.V., Leiden 2333 CH, the Netherlands.
Stephan TheisgenZoBio B.V., Leiden 2333 CH, the Netherlands.
Nicole GruenheitCeGaT GmbH, Tübingen 72076, Germany.
Saskia BiskupCeGaT GmbH, Tübingen 72076, Germany.
Matthias SchwabDr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart 70376, Germany; iFIT Cluster of Excellence (EXC 2180) "Image-guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen 72076, Germany; Department of Clinical Pharmacology, Pharmacy and Biochemistry, University of Tübingen, Tübingen 72076, Germany.
Wolfgang AlbrechtHepaRegeniX GmbH, Tübingen 72072, Germany.
Stefan LauferDepartment of Pharmaceutical Chemistry, University of Tübingen, Tübingen 72076, Germany; Tübingen Center for Academic Drug Discovery & Development (TüCAD(2)), Tübingen 72076, Germany. Electronic address: stefan.laufer@uni-tuebingen.de.
Scott NybergWilliam J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: nyberg.scott@mayo.edu.
Lars ZenderDepartment of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, Tübingen 72076, Germany; iFIT Cluster of Excellence (EXC 2180) "Image-guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen 72076, Germany; German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Tübingen Center for Academic Drug Discovery & Development (TüCAD(2)), Tübingen 72076, Germany. Electronic address: lars.zender@med.uni-tuebingen.de.
Mayo Clinic · USUniversity Children's Hospital Tübingen · DEDr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology · DEUniversity of Tübingen · DECeGaT (Germany) · DEGerman Cancer Research Center · DEAgency for Science, Technology and Research · SGBernstein Center for Computational Neuroscience Tübingen · DEHeidelberg University · DEUniversity of Eastern Finland · FI
Funding
Immunodeficient FAH-/- PigsR01DK106667 · NIDDK · MAYO CLINIC ROCHESTER · PI NYBERG, SCOTT L · 2015 to 2019
$2.1MNIDDK NIH HHS R01 DK106667
Abstract
Diminished hepatocyte regeneration is a key feature of acute and chronic liver diseases and after extended liver resections, resulting in the inability to maintain or restore a sufficient functional liver mass. Therapies to restore hepatocyte regeneration are lacking, making liver transplantation the only curative option for end-stage liver disease. Here, we report on the structure-based development and characterization (nuclear magnetic resonance [NMR] spectroscopy) of first-in-class small molecule inhibitors of the dual-specificity kinase MKK4 (MKK4i). MKK4i increased liver regeneration upon hepatectomy in murine and porcine models, allowed for survival of pigs in a lethal 85% hepatectomy model, and showed antisteatotic and antifibrotic effects in liver disease mouse models. A first-in-human phase I trial (European Union Drug Regulating Authorities Clinical Trials [EudraCT] 2021-000193-28) with the clinical candidate HRX215 was conducted and revealed excellent safety and pharmacokinetics. Clinical trials to probe HRX215 for prevention/treatment of liver failure after extensive oncological liver resections or after transplantation of small grafts are warranted.
Indexed as
Enzyme InhibitorsLiver FailureMAP Kinase Kinase 4AnimalsHepatectomyHepatocytesHumansLiverLiver DiseasesLiver RegenerationMiceSwineEnzyme InhibitorsMAP Kinase Kinase 4drug discovery and developmentfirst-in-human phase I trialliverliver failureliver regenerationMKK4partial hepatectomy
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.