SpliceBind: Isoform-Aware Prediction of Binding Pocket Druggability

• URL: http://arxiv.org/abs/2606.04020v1
• Date: Mon, 01 Jun 2026 09:21:24 GMT
• Title: SpliceBind: Isoform-Aware Prediction of Binding Pocket Druggability
• Abstract summary: We introduce a graph neural network framework for bridging-aware druggability prediction.<n> Systematic analysis of six clinically validated variants spanning five mechanism classes reveals a two-tier resistance taxonomy.<n>On 229 kinase pockets spanning 25 families, SpliceBind achieves AUROC 0.703 with robust to held-out families.
• Score: 0.0
• License: http://creativecommons.org/licenses/by/4.0/
• Abstract: Splice-mediated drug resistance occurs in up to 40% of patients on targeted kinase inhibitors, yet state-of-the-art druggability tools operate on single structures and cannot compare across isoforms. We introduce SpliceBind, a graph neural network framework for isoform-aware druggability prediction. Beyond improving prediction accuracy (AUROC 0.703 vs. P2Rank 0.634, p = 0.026), we address a more fundamental question: when do structural methods succeed, and when must they fail? Systematic analysis of six clinically validated variants spanning five mechanism classes reveals a two-tier resistance taxonomy. Domain deletions (AR-V7, Delta = -18.39) and pocket disruptions produce structurally detectable changes, while allosteric mechanisms (BRAF-p61) remain fundamentally invisible to any pocket-centric approach -- a boundary no algorithmic improvement can cross. Notably, learned embeddings capture affinity-based resistance missed by geometry alone (ALK-L1196M: Delta_SB = -0.228 vs. Delta_P2Rank = -0.95), partially bridging the structural-biochemical gap. On 229 kinase pockets spanning 25 families, SpliceBind achieves AUROC 0.703 (p = 0.026 vs. P2Rank) with robust generalization to held-out families (AUROC 0.761). This taxonomy transforms clinical workflows: upon discovering a splice variant, clinicians can immediately determine whether computational triage suffices or biochemical validation is required -- reducing time from variant discovery to therapeutic decision.

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