Phenotypic screening identifies kenpaullone as a prolymphangiogenic compound to improve heart repair following myocardial infarction
4 affiliations
- 1Institute of Developmental and Regenerative Medicine, University of Oxford, Oxford OX3 7TY, United Kingdom
- 2Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom
- 3Department of Pharmacology, University of Oxford, Oxford OX1 3QT, United Kingdom
- 4Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford OX1 3TA, United Kingdom
Abstract
Myocardial infarction (MI) induces cardiac muscle death and its subsequent replacement by a noncontractile fibrotic scar, which underlies progression to heart failure. Current treatments restore blood flow and assist with cardiac workload but do not promote regeneration. We have previously shown endogenous growth of the cardiac lymphatic system following MI and further stimulation with the lymphatic endothelial specific mutated Vascular Endothelial Growth Factor-C (VEGF-C) isoform, VEGFC-C156S, resolves the immune response and improves cardiac function. However, the short half-life of VEGFC-C156S makes it suboptimal for clinical use, highlighting the need for alternative prolymphangiogenic strategies. We established a spheroid-based sprouting assay using human lymphatic endothelial cells to mimic lymphangiogenesis and performed a phenotypic screen of focused libraries of epigenetic regulators, kinase inhibitors, and stem cell modulators. Automated imaging and quantitative analysis identified several kinase inhibitors, previously characterized as GSK3ß inhibitors, as prolymphangiogenic regulators. Among them, the most potent was kenpaullone, which activated the same canonical prolymphangiogenic ERK pathway as VEGF-C, but induced a distinct transcriptional response in treated spheroids. Using kenpaullone-derived chemical probes and target-validation approaches, we identified MAP4K4 as a molecular target mediating the prolymphangiogenic effect observed. Finally, in a mouse MI model, kenpaullone enhanced cardiac lymphangiogenesis and improved cardiac function.
Related
- Cross-cohort blood transcriptome analysis identifies an eight-gene diagnostic index and inflammatory programs in acute myocardial infarction
- ECG-Derived Synthetic Left Ventricular Mechanics Predict Mortality After Acute Myocardial Infarction and Fatal Myocardial Infarction in the General Population
- Beta-Blocker Therapy After Acute Myocardial Infarction
- The Korea Acute Myocardial Infarction Registry: Two Decades of AMI Care in Korea.
- Role of Inflammation in the Development of Heart Failure After Myocardial Infarction
BibTeX
@article{ravaud2026phenotypic,
title = {{Phenotypic screening identifies kenpaullone as a prolymphangiogenic compound to improve heart repair following myocardial infarction}},
author = {Christophe Ravaud and Caroline A. Cuoco and Sarah Sigal and Hannah M. Unsworth and Susanna T. E. Cooper and Adam B. Lokman and Carole J. R. Bataille and Angela J. Russell and Paul R. Riley},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2619427123},
url = {https://doi.org/10.1073/pnas.2619427123},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Phenotypic screening identifies kenpaullone as a prolymphangiogenic compound to improve heart repair following myocardial infarction
AU - Christophe Ravaud
AU - Caroline A. Cuoco
AU - Sarah Sigal
AU - Hannah M. Unsworth
AU - Susanna T. E. Cooper
AU - Adam B. Lokman
AU - Carole J. R. Bataille
AU - Angela J. Russell
AU - Paul R. Riley
PY - 2026
DA - 2026/10/06
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2619427123
UR - https://doi.org/10.1073/pnas.2619427123
AB - Myocardial infarction (MI) induces cardiac muscle death and its subsequent replacement by a noncontractile fibrotic scar, which underlies progression to heart failure. Current treatments restore blood flow and assist with cardiac workload but do not promote regeneration. We have previously shown endogenous growth of the cardiac lymphatic system following MI and further stimulation with the lymphatic endothelial specific mutated Vascular Endothelial Growth Factor-C (VEGF-C) isoform, VEGFC-C156S, resolves the immune response and improves cardiac function. However, the short half-life of VEGFC-C156S makes it suboptimal for clinical use, highlighting the need for alternative prolymphangiogenic strategies. We established a spheroid-based sprouting assay using human lymphatic endothelial cells to mimic lymphangiogenesis and performed a phenotypic screen of focused libraries of epigenetic regulators, kinase inhibitors, and stem cell modulators. Automated imaging and quantitative analysis identified several kinase inhibitors, previously characterized as GSK3ß inhibitors, as prolymphangiogenic regulators. Among them, the most potent was kenpaullone, which activated the same canonical prolymphangiogenic ERK pathway as VEGF-C, but induced a distinct transcriptional response in treated spheroids. Using kenpaullone-derived chemical probes and target-validation approaches, we identified MAP4K4 as a molecular target mediating the prolymphangiogenic effect observed. Finally, in a mouse MI model, kenpaullone enhanced cardiac lymphangiogenesis and improved cardiac function.
SN - 0027-8424
SN - 1091-6490
ER -