Repurposed cancer and blood pressure drugs show promise against artery-clogging foam cells

Atherosclerosis, the slow and silent narrowing of the arteries that underlies most heart attacks and strokes, remains the world’s leading cause of death, and researchers continue to search for ways to interrupt the earliest cellular events that set the disease in motion. One of the most critical of those events is the transformation of macrophages, immune cells that patrol the arterial wall, into lipid-laden foam cells. When macrophages engulf excessive amounts of oxidized low-density lipoprotein, or oxLDL, they swell with cholesteryl esters and become the fatty streaks that mark the first visible stage of plaque formation. A new study from the Dr. B.R. Ambedkar Center for Biomedical Research at the University of Delhi, published in the journal Molecular Diversity, takes aim at this process through an unexpected route: recycling drugs that were originally designed to treat cancer and high blood pressure.

The research, led by Prerna Bansal and supervised by Kamna Srivastava, focused on a signaling protein called VAV2. VAV2 is a guanine nucleotide exchange factor, a molecular switch that activates Rho-family GTPases such as Cdc42, Rac1 and RhoA by exchanging GDP for GTP. These small GTPases regulate the actin cytoskeleton, cell spreading, migration and signaling, and previous work has implicated the Vav family in the uptake of oxidized lipoproteins and in the development of atherosclerotic lesions in mice. Genetic studies have linked VAV2 and its close relative VAV3 to cardiovascular risk factors in humans, and mice lacking Vav2 develop cardiovascular abnormalities, making the protein a biologically plausible, if challenging, drug target.

Targeting VAV2 with conventional drug discovery would be slow and expensive, so the team turned to structure-based drug repurposing, a strategy that asks whether approved or clinically tested medicines already possess the right molecular shape and chemistry to engage a new target. Repurposing offers a well-known advantage: because repurposed candidates have established safety, pharmacokinetic and manufacturing profiles, they can move into new indications far faster than de novo chemical entities. Building on the group’s earlier work that identified repurposed drugs as disruptors of the PCSK9-LDLR axis for lipid lowering, the researchers set out to find compounds capable of interfering with the VAV2 signaling that supports foam-cell formation.

Because a full experimental structure of human VAV2 spanning all of its domains, including the calponin homology, Dbl homology, pleckstrin homology and regulatory regions, was not available, the team constructed a full-length three-dimensional structural model of the protein. Predicted protein structures of this kind, an approach validated by the success of modern deep-learning structure prediction, provide a scaffold for computational ligand screening even when crystallography has not delivered a target structure. The researchers then assembled libraries of clinically relevant compounds, drawing on FDA-approved drug collections and curated chemical databases, and screened them computationally against the VAV2 model to find molecules with predicted binding affinity.

The computational funnel was deliberately stringent. Virtual screening narrowed thousands of candidates, and molecular docking with AutoDock Vina estimated how each ligand might sit within pockets on the VAV2 model. Surviving compounds were then filtered for drug-likeness and predicted pharmacokinetics using established rules for solubility, permeability and molecular descriptors, together with graph-based predictions of absorption, distribution, metabolism, excretion and toxicity. The top-ranked candidates, which included the PARP inhibitor talazoparib, the VEGF receptor inhibitor tivozanib and the calcium channel blocker isradipine, were then subjected to an unusually thorough dynamic assessment: three independent 200-nanosecond molecular dynamics simulations for each protein-ligand complex, run with the GROMACS engine under constant pressure and temperature conditions.

Those simulations allowed the team to ask whether the predicted binding poses were physically stable or merely computational artifacts. Root mean square deviation and radius of gyration measurements tracked the overall convergence and compactness of each complex, while root mean square fluctuation analyses revealed how flexibly individual residues behaved in the bound state. Principal component analysis distilled the dominant collective motions of the protein-ligand systems, and binding free energies were estimated with the molecular mechanics Poisson-Boltzmann surface area method, which decomposes affinity into van der Waals, electrostatic, polar and non-polar solvation contributions. Across these measures, talazoparib, tivozanib and isradipine consistently emerged as the most stable and energetically favorable VAV2 binders among the screened set.

Computation alone, however, cannot establish biological activity, so the investigators moved to cell-based experiments using THP-1 human monocytic cells differentiated into macrophages with phorbol 12-myristate 13-acetate. When these macrophages were exposed to oxidized LDL, they accumulated intracellular neutral lipids, mimicking the foam-cell transformation that occurs in the arterial wall. Treating the cells with talazoparib significantly reduced that oxLDL-induced neutral-lipid accumulation at a concentration that was sub-cytotoxic, meaning the effect could not be explained simply by the drug killing the cells. Cell viability was independently monitored using an MTT assay, an established colorimetric measure of metabolic activity.

A complementary experiment strengthened the case. In a DiI-oxLDL uptake assay, in which oxidized lipoprotein particles are fluorescently labeled so that their binding and internalization can be quantified, all three compounds, talazoparib, tivozanib and isradipine, reduced cell-associated fluorescence relative to vehicle-treated controls. This suggests that each candidate interferes with some step in the handling of oxidized lipoproteins by macrophages, whether at the level of receptor engagement, actin-dependent internalization or downstream signaling through the VAV2 pathway. The consistency between the structural predictions and the cellular readouts is what lends the study its persuasive weight, since purely computational hits frequently fail at this transition.

The authors are careful to frame these results as preliminary. Direct physical binding of any of the three compounds to VAV2 has not been demonstrated biochemically, and no direct inhibition of VAV2’s exchange-factor activity has been measured. The observed reductions in lipid accumulation could, in principle, arise from mechanisms unrelated to VAV2, a possibility that is particularly relevant for isradipine, a calcium channel blocker with well-documented vascular effects, and for talazoparib, whose primary target is the DNA repair enzyme PARP. Confirming the mechanism will require biochemical binding assays, genetic knockdown or knockout experiments, pharmacological controls and, ultimately, in vivo studies in animal models of atherosclerosis.

Even with those caveats, the work illustrates how modern computational pipelines can compress the earliest phase of drug discovery for a notoriously difficult target class. Signaling proteins like VAV2, with their large multidomain architectures and dynamic regulatory conformations, are rarely the first choice for small-molecule drug development, yet the combination of full-length structural modeling, rigorous multi-replica simulation and rapid cellular validation produced three clinically familiar candidates worthy of deeper study. If subsequent biochemical and animal work confirms that talazoparib, tivozanib or isradipine can suppress foam-cell formation through VAV2 or an allied pathway, the field would gain a shortcut to anti-atherosclerotic therapy that bypasses a decade of de novo chemistry. For now, the study stands as a proof of concept that drug repurposing, guided by structure and validated in human macrophages, can surface plausible new weapons against the cellular origins of the world’s deadliest disease.

Subject of Research: Drug repurposing against VAV2 to block macrophage foam-cell formation in atherosclerosis

Article Title: Structure-based drug repurposing and in vitro evaluation of VAV2-associated candidates for suppression of macrophage foam-cell formation in atherosclerosis

Article References: Structure-based drug repurposing and in vitro evaluation of VAV2-associated candidates for suppression of macrophage foam-cell formation in atherosclerosis. (n.d.). https://doi.org/10.1007/s11030-026-11713-0

Image Credits: AI Generated

DOI: 10.1007/s11030-026-11713-0

Keywords: VAV2, atherosclerosis, foam cells, drug repurposing, molecular docking, molecular dynamics, oxLDL, talazoparib, tivozanib, isradipine, macrophages, cardiovascular disease