Leukemia drug Ponatinib shrinks hypertrophic heart cells in early lab test

A drug already approved to treat leukemia has shown early signs of being able to counteract cardiac hypertrophy, the abnormal enlargement of heart cells that paves the way toward heart failure. In a new study published in Discover Pharmaceutical Sciences, researchers in India combined computer-based network pharmacology, molecular docking simulations, and experiments in rat heart-derived cells to probe whether Ponatinib, a multi-targeted tyrosine kinase inhibitor, could dampen the signaling networks that drive pathological cardiac growth. The work is explicitly preliminary, but it offers a structured first look at a repurposing hypothesis that has not previously been tested directly.

Cardiac hypertrophy develops as a pathological response to sustained cardiovascular stressors such as myocardial infarction, chronic systemic hypertension, valvular heart disease, and persistent inflammatory processes. It is defined as a prolonged increase in cardiac mass and involves significant alterations in protein synthesis, cellular enlargement, contractile activity, collagen production, and fibrotic remodeling. Cardiac fibroblasts, the most abundant cell type in adult heart tissue, are central to this process: when activated, they can transform into myofibroblasts, a pivotal step in fibrotic progression that can lead to chamber dilation, cardiomyocyte hypertrophy, cell death, and eventually congestive heart failure.

Ponatinib was an intriguing candidate for several reasons. The drug is a clinically approved multi-targeted tyrosine kinase inhibitor used primarily to treat different types of leukemia, and it is known to inhibit multiple pro-fibrotic growth factor receptors, including VEGFR, PDGFR, and FGFR, which are implicated in fibrotic and hypertrophic signaling pathways. Previous studies have shown that Ponatinib modulates several growth factor-mediated pathways, including PDGFR, VEGFR, MAPK, PI3K-Akt, and JAK/STAT signaling, all of which are critically involved in cardiomyocyte hypertrophy, inflammation, apoptosis, and cardiac dysfunction. The authors also note that recent evidence has associated Ponatinib-induced cardiotoxicity with dysregulation of autophagy, connexin-43 signaling, cellular senescence, and survival-related pathways, indicating that the drug directly influences molecular mechanisms involved in cardiac remodeling. Until now, however, its independent effect on hypertrophic signaling networks had not been investigated as a standalone therapy.

To map the drug’s potential reach, the team first assembled a comprehensive target list. Searches of the PubChem, Swiss Target Prediction, and SuperPred databases yielded 45 main targets from Super-PRED and 100 from Swiss Target Prediction, which after deduplication produced 107 unique Ponatinib-associated candidate targets. For the disease side, keyword searches of GeneCards and OMIM retrieved 1,187 and 310 genes respectively, giving 1,324 genes after deduplication, standardized to 1,192 protein-coding genes using the HUGO database. The intersection of the two sets contained 24 shared targets, which the researchers then fed into the STRING database to build a protein–protein interaction network at the highest confidence threshold of 0.95, visualized and analyzed in Cytoscape with the CytoHubba plugin.

From that network, five hub proteins emerged as the most topologically important, identified by degree, betweenness centrality, and closeness centrality values exceeding their respective thresholds: EGFR, MAPK8, MAP3K7, JAK2, and PDGFRB. Gene Ontology and KEGG pathway enrichment analyses pointed toward MAPK and PI3K-Akt signaling as the dominant pathways connecting these targets to cardiac hypertrophy, along with cytokine signaling. The authors note that these proteins are known regulators of fibroblast activation, extracellular matrix deposition, and hypertrophic remodeling, which underscores why their convergence around a single drug candidate attracted attention.

Molecular docking was then used to test how strongly Ponatinib binds to the five hub proteins. Using AutoDock Vina with an active-site docking approach based on the co-crystallized ligand binding pockets of EGFR (PDB 8SC7), PDGFRB (PDB 1H9O), MAPK8 (PDB 8X5M), MAP3K7 (PDB 5V5N), and JAK2 (PDB 6VN8), the simulations produced binding energies ranging from −9.1 to −12.3 kcal/mol. PDGFRB showed the strongest predicted affinity at −12.3 kcal/mol, followed by JAK2 at −11.5 kcal/mol, while MAPK8 and EGFR each scored −9.4 kcal/mol and MAP3K7 −9.1 kcal/mol. The docking poses were visualized in Biovia Discovery Studio 2024, revealing conventional hydrogen bonds and extensive van der Waals contacts with specific residues in each binding pocket. These are computational predictions, not measurements of biological activity, but they suggest that PDGFRB and JAK2 may serve as primary mediators of Ponatinib’s activity in this context.

The experimental validation used H9C2 (2–1) cells, a rat cardiomyoblast cell line obtained from the National Centre for Cell Science in Pune, India. In an initial viability screen, cells were treated with Ponatinib at 0.25, 0.5, and 1 µM for 24 hours and assessed with an MTT assay. Only the highest concentration, 1 µM, significantly reduced cell viability compared with the untreated control, so 0.25 µM was selected as the concentration with the highest viability for subsequent experiments, along with lower doses of 0.20, 0.15, 0.10, and 0.05 µM to evaluate potential dose-dependent effects.

Hypertrophy was then induced by exposing the cells to a high-salt medium consisting of DMEM supplemented with an additional 130 mM NaCl, achieving a final sodium concentration of 240 mM, while a normal control group received standard medium. After 48 hours, high-salt treatment had significantly increased cell size in the disease control group compared with the normal control (p = 0.0001). Treatment with Ponatinib at 0.25 µM and 0.20 µM significantly reduced cell area relative to the disease control, while maintaining cell viability. The α-SMA level, measured by ELISA in culture supernatants as a marker of cardiac fibrosis, was significantly elevated by high-salt treatment, but no significant variation was observed among the various Ponatinib treatment concentrations. The authors interpret this as indicating that Ponatinib’s protective effect operates primarily through attenuation of hypertrophic signaling rather than through the fibrotic marker measured here.

The study’s limitations are substantial and the authors enumerate them candidly. The network pharmacology and docking analyses are in silico predictions that may not capture the complexity of biological systems, and mechanistic validation of the PDGFR and JAK/STAT pathways was not performed with techniques such as Western blotting or gene expression analysis. The H9C2 cell line, while widely used, does not completely replicate the physiological behavior of primary cardiac fibroblasts or the in vivo cardiac environment. Importantly, because Ponatinib is known for anti-proliferative activity, the observed reduction in cell size may partially reflect inhibition of cellular proliferation rather than a purely anti-hypertrophic effect. The experiments were also conducted in medium supplemented with 10% fetal bovine serum, which contains multiple growth factors that activate hypertrophic signaling, and since Ponatinib targets several receptor tyrosine kinases involved in growth factor signaling, the influence of serum-derived factors on the observed responses cannot be excluded. The authors call for future studies using serum-starved conditions, non-proliferative cardiomyocyte models such as primary neonatal or adult cardiomyocytes, and animal models to validate both the therapeutic potential and the safety profile.

Even with those caveats, the convergence of the three lines of evidence — a target network centered on growth factor receptors, strong predicted binding to PDGFRB and JAK2, and a measurable reduction in high-salt-induced cell enlargement at a non-toxic concentration — provides a coherent, if early, rationale for repurposing Ponatinib as an anti-hypertrophic agent. The narrow therapeutic window is a recurring theme: 0.25 µM was protective, while 1 µM was cytotoxic, and the authors emphasize that careful dose optimization and safety evaluation will be necessary before any consideration of cardiovascular applications. As a first computational and cellular sketch of an untested hypothesis, the study maps the terrain that future animal and mechanistic work will need to cover.

Subject of Research: Repurposing the leukemia drug Ponatinib as a potential therapy for cardiac hypertrophy

Article Title: Network pharmacology, molecular docking, and preliminary in vitro evaluation of Ponatinib in cardiac hypertrophy

Article References: Prajapati, A. K., Shah, G., & Gajjar, N. (2026). Network pharmacology, molecular docking, and preliminary in vitro evaluation of Ponatinib in cardiac hypertrophy. Discover Pharmaceutical Sciences, 2(1), Article 21. https://doi.org/10.1007/s44395-026-00050-8

Image Credits: AI Generated

DOI: 10.1007/s44395-026-00050-8

Keywords: Ponatinib, cardiac hypertrophy, network pharmacology, molecular docking, drug repurposing, H9C2 cells, PDGFRB, JAK2, tyrosine kinase inhibitor, heart failure, α-SMA, in vitro study