Background
Although functional genomics has expanded the list of candidate cancer vulnerabilities, identifying which dependencies are therapeutically relevant – and successfully drugging them – remains a central challenge across cancers. To bridge this gap, we developed ChemProTarget – a cancer-agnostic pipeline that integrates chemoproteomics and functional genomics to prioritise cancer dependencies and pair them with covalent small-molecule probes. While validated in paediatric cancers, the framework is broadly applicable, with the goal of releasing an interactive web platform in 2026 to enable the wider community to explore targetable disease-relevant vulnerabilities.
Methods and Findings
ChemProTarget integrated chemoproteomic libraries of covalent probes with functional genomics, identifying 65 and 72 cancer specific dependencies for neuroblastoma and medulloblastoma respectively. Two dependencies were prioritised: IGF2BP3, an RNA-binding protein regarded as undruggable and never previously demonstrated as a neuroblastoma dependency; and SAFB2, a virtually unstudied DNA/RNA-binding protein with no established roles in cancer.
Initial drug screens revealed potent, cancer-selective small molecules that spared non-malignant cells. Synergy with siRNA depletion supported on-target engagement, while CETSA confirmed direct in-cell binding of the covalent molecules to IGF2BP3 and SAFB2. RNA-immunoprecipitation further demonstrated disruption of IGF2BP3 and SAFB2-RNA complexes. Importantly, all validations were performed in cell-based models, ensuring biological relevance.
Multi-omic profiling revealed convergence between siRNA and probe treatments. In neuroblastoma, IGF2BP3 inhibition suppressed MYC signalling, G2M checkpoint, and ROS pathways, validating its role as a novel neuroblastoma driver. In medulloblastoma, SAFB2 inhibition downregulated IL2-STAT5 and EMT pathways across transcriptomic and proteomic levels, establishing SAFB2 as a novel medulloblastoma dependency.
Conclusion
By integrating chemoproteomics and functional genomics, ChemProTarget bridges a major translation gap in oncology and drug discovery. This pipeline uncovers druggable entry points for previously undruggable drivers as well as completely novel cancer vulnerabilities. Its cancer-agnostic design, combined with a forthcoming open-access platform, positions ChemProTarget as a drug discovery platform for uncovering druggable targets across paediatric and adult cancers.