The therapeutic potential of targeted protein degradation (TPD) is tempered by on-target toxicity in critical tissues, creating a major bottleneck for degrader translation. To address this, we developed TissueSAFE, an integrative platform that unites our expert-curated E3-ome with single-cell RNA-seq and tissue proteomic datasets to map the expression of E3 ligases across human biology. TissueSAFE enables the identification of ligases selectively expressed in disease contexts while sparing vulnerable cell types, thereby guiding degrader design with a precision not previously possible.
Through an interactive Shiny-based interface, users can interrogate ligase expression across tissues, cell subtypes, and disease states, rapidly prioritising candidates for tissue-selective or cell-type-specific degrader development. Proof-of-concept analyses demonstrate that TissueSAFE can generate actionable hypotheses, with output validated in experimental models. While initially applied to prostate cancer, its scope extends to diverse disease modalities and across both oncology and non-oncology contexts.
By merging high-resolution expression data with degrader biology, TissueSAFE offers a scalable framework to overcome toxicity barriers, accelerate rational degrader design, and uncover new ligase opportunities. We present this platform and supporting experimental validation as a new approach to integrating discovery biology with translational degrader development, opening a path to safer and more selective TPD therapeutics.