Virtual screening uncovers tepotinib as LY75 inhibitor against ovarian cancer

In a finding that could reshape the search for new treatments against one of the deadliest gynecologic malignancies, researchers in Shanghai have identified the approved lung cancer drug tepotinib as a potent inhibitor of ovarian cancer growth, acting through an unexpected molecular target known as LY75. The study, published in the Journal of Ovarian Research, combines large-scale computational screening, structural biology, and preclinical testing to make a case for repurposing an existing medicine against a disease that urgently needs new options.

Ovarian cancer remains one of the most lethal cancers affecting women, largely because it is often diagnosed at an advanced stage and because resistance to platinum-based chemotherapy and PARP inhibitors eventually develops in most patients. High-grade serous ovarian cancer, the most common and aggressive subtype, has proven particularly stubborn, and survival rates have improved only marginally over recent decades. Against this backdrop, the idea of finding new uses for drugs that have already passed safety testing in humans, a strategy known as drug repurposing, has gained considerable traction. The new study demonstrates how modern computational tools can accelerate that process dramatically.

The research team, led by Yang Xiao, Wei Xia, and Yanan Song of Pudong Gongli Hospital and the Shanghai University of Medicine and Health Sciences, began by focusing on LY75, also known as CD205 or DEC205, a C-type lectin receptor best known for its role in antigen uptake by dendritic cells. Mining data from The Cancer Genome Atlas and the Human Protein Atlas, the investigators found that LY75 was significantly upregulated in ovarian cancer tissues compared with healthy tissue. More importantly, elevated LY75 expression correlated with shorter progression-free survival, marking the protein as both a potential biomarker of aggressive disease and an attractive therapeutic target.

With the target in hand, the team turned to structure-based virtual screening. Rather than testing thousands of compounds in the laboratory, they used the published crystal structure of the LY75 protein, deposited in the Protein Data Bank under the identifier 8K8H, as a template to computationally dock molecules from the TargetMol compound library. Docking predicts how well a small molecule fits into a binding pocket on a protein, but the researchers went considerably further. They applied MM/GBSA calculations, a method that estimates binding free energy by combining molecular mechanics forces with implicit solvent models, to rescore candidate poses. They also employed protein-ligand interaction fingerprints, or PLIF analysis, to compare the binding patterns of candidates against known interaction motifs, and ran ADMET predictions to filter out compounds likely to fail on absorption, metabolism, or toxicity grounds before any experiment was performed.

From this computational funnel, tepotinib emerged as the leading candidate. Tepotinib is an orally available small molecule approved in several countries for the treatment of non-small cell lung cancer harboring MET exon 14 skipping mutations, where it acts as a MET kinase inhibitor. Its appearance as a strong LY75 binder raised an obvious question: was any anti-cancer effect simply a consequence of MET inhibition? The team anticipated this concern and designed their study around it, measuring c-MET expression in their cell models, examining MET–LY75 co-expression patterns, and running parallel pharmacological controls with capmatinib, another selective MET inhibitor, to disentangle the two mechanisms.

The laboratory experiments delivered striking results. Tepotinib preferentially inhibited ovarian cancer cell lines with high LY75 expression, achieving half-maximal inhibitory concentrations, or IC₅₀ values, of 16.31 micromolar in SKOV3 cells and 18.91 micromolar in OVCAR-8 cells. In contrast, the drug showed markedly weaker activity against HO8910 cells, which express low levels of LY75, a dose-response pattern consistent with LY75 serving as the drug’s relevant target rather than an incidental one. To confirm a direct physical interaction, the researchers turned to surface plasmon resonance, a label-free optical technique that measures real-time binding between molecules immobilized on a sensor surface. The experiments confirmed that tepotinib binds LY75 directly, with a kinetic dissociation constant of 2.52 micromolar and a steady-state K_D of 3.74 micromolar, values indicating a specific and measurable interaction.

Perhaps the most intriguing mechanistic finding concerns what tepotinib does to the LY75 protein once bound. Treatment with the drug induced apoptosis in the sensitive cell lines, suppressed their migratory capacity, a process closely tied to metastatic spread, and downregulated LY75 protein levels. When the team probed how this downregulation occurred, they found that tepotinib accelerated LY75 degradation through a pathway that does not depend on the ubiquitin-proteasome system, the cell’s standard machinery for tagging unwanted proteins for destruction. Cycloheximide chase experiments, which block new protein synthesis and allow the decay rate of existing proteins to be measured, supported this conclusion. The identity of the alternative degradation route remains an open question, but the observation suggests tepotinib may engage lysosomal or autophagic pathways, a hypothesis that will require further work to confirm.

The in vivo evidence proved even more compelling. In mouse xenograft models implanted with SKOV3 ovarian cancer cells, oral administration of tepotinib markedly suppressed tumor growth, achieving a tumor inhibition rate of 79.6 percent. Analysis of the excised tumors showed reduced LY75 expression in the treated animals, consistent with the drug engaging its target in living tissue. All animal procedures were approved by the Institutional Animal Care and Use Committee of Shanghai Health Medical College and conducted in accordance with the ARRIVE guidelines for reporting animal research.

Crucially, the MET controls strengthened rather than weakened the case for LY75 as the operative target. Capmatinib, a structurally distinct MET inhibitor, failed to reproduce the full anti-tumor activity of tepotinib in the ovarian cancer models, and analyses of c-MET expression and MET–LY75 co-expression in patient datasets suggested that MET inhibition alone could not account for the magnitude of benefit observed. The authors therefore conclude that tepotinib’s effect in ovarian cancer reflects a genuine dual pharmacology, with LY75 binding and subsequent LY75 protein downregulation contributing substantially to its activity.

The implications of the study extend in several directions. First, it elevates LY75 from an immunological curiosity to a candidate therapeutic target in ovarian cancer, a protein whose abundance in tumors and association with poor prognosis make it a marker worth tracking clinically. LY75 has already attracted attention in oncology as a target for antibody-drug conjugates, given its presence on the surface of certain tumor cells and its efficient internalization, and the new findings add a small-molecule dimension to that conversation. Second, the work offers a template for computational drug repurposing: crystal-structure-guided docking, energy-based rescoring, interaction fingerprinting, and ADMET filtering followed by rigorous biochemical and in vivo validation. The approach identifies candidates in silico in a fraction of the time and cost of conventional screening campaigns.

Third, and most immediately, the results argue for clinical exploration of tepotinib in ovarian cancer, particularly in patients whose tumors express high levels of LY75. Because the drug is already approved and its safety profile in humans is documented, the path from laboratory finding to clinical trial is potentially shorter than for a de novo compound. The micromolar potencies observed in cell culture are modest by the standards of modern targeted therapy, and patients would likely require careful dosing studies, biomarker-based selection, and possibly drug combinations to translate the xenograft results into human benefit. Questions also remain about whether the ubiquitin-proteasome-independent degradation mechanism operates identically in human tumors and about the precise structural features of the tepotinib–LY75 interaction that could be optimized in next-generation analogs.

The study is not without limitations, as its authors acknowledge. The work relies on cell lines and xenografts rather than patient-derived models, and the correlation between LY75 expression and drug sensitivity, while suggestive, has been established across only a handful of cell lines. Prospective validation in patient-derived xenografts and organoids, ideally stratified by LY75 expression, would sharpen the biomarker hypothesis considerably. Nonetheless, the convergence of computational prediction, biochemical confirmation, mechanistic insight, and animal efficacy data makes this one of the more complete preclinical repurposing cases published for ovarian cancer in recent memory.

For a disease in which the therapeutic arsenal has expanded slowly and resistance is nearly universal, the prospect that a drug already sitting on pharmacy shelves could be redirected against a newly validated molecular target is the kind of story that resonates far beyond the laboratory. If follow-up studies and early-phase trials bear out these findings, tepotinib’s second act may prove more consequential than its first, and LY75 may take its place among the actionable targets of precision oncology.