ProMeta: Few-shot PROTAC-targeted degradation prediction across E3 ligases
Abstract
Proteolysis-targeting chimeras (PROTACs) have emerged as a transformative therapeutic strategy that selectively degrades historically ''undruggable'' targets via the ubiquitin-proteasome system. Despite growing efforts to develop computational predictors of PROTAC degradation activity, existing supervised approaches remain severely challenged by data scarcity and imbalance across E3 ligases, limiting their ability to generalize beyond well-studied ligase contexts. In practice, labeled data are heavily concentrated on a few ligases (e.g., CRBN and VHL), while the majority of E3 ligases remain underexplored yet are critical for expanding the design space of targeted degraders. Developing methods that enable robust cross-ligase generalization with minimal labeled data is therefore essential for improving the practical utility of computational PROTAC discovery. We reformulate PROTAC degradation activity prediction across E3 ligases as a few-shot meta-learning problem and present ProMeta, a prototype-based graph neural network trained through episodic meta-learning on source-E3 tasks and evaluated on held-out target-E3 tasks through support-conditioned inference. ProMeta performs inference without updating the encoder by dynamically estimating class prototypes from minimal target-ligase support samples. On the CRBN-to-VHL benchmark, ProMeta achieves AUROC values of 0.796 under K=2, Q=3 and 0.883 under K=2, Q=5, improving by 19.9% and 6.8%, respectively, over the corresponding supervised GNN baseline. Reverse VHL-to-CRBN transfer under the same protocol yielded AUROC values of 0.702 (K=2, Q=3) and 0.821 (K=2, Q=5), confirming bidirectional applicability while revealing direction and data-regime dependence. Together, these results support ProMeta as a practical framework for cross-ligase few-shot prediction under the evaluated support/query protocols.
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BibTeX
@misc{liu2026prometa,
title = {{ProMeta: Few-shot PROTAC-targeted degradation prediction across E3 ligases}},
author = {Yuansheng Liu and Yufei Ye and Tao Tang and Jiawei Luo and Wen Tao and Xiao Luo},
howpublished = {arXiv},
year = {2026},
month = sep,
doi = {10.48550/arxiv.2609.09891},
eprint = {2609.09891},
archivePrefix = {arXiv},
url = {https://arxiv.org/abs/2609.09891},
}
RIS
TY - UNPB
TI - ProMeta: Few-shot PROTAC-targeted degradation prediction across E3 ligases
AU - Yuansheng Liu
AU - Yufei Ye
AU - Tao Tang
AU - Jiawei Luo
AU - Wen Tao
AU - Xiao Luo
PY - 2026
DA - 2026/09/09
PB - arXiv
DO - 10.48550/arxiv.2609.09891
UR - https://arxiv.org/abs/2609.09891
AB - Proteolysis-targeting chimeras (PROTACs) have emerged as a transformative therapeutic strategy that selectively degrades historically ''undruggable'' targets via the ubiquitin-proteasome system. Despite growing efforts to develop computational predictors of PROTAC degradation activity, existing supervised approaches remain severely challenged by data scarcity and imbalance across E3 ligases, limiting their ability to generalize beyond well-studied ligase contexts. In practice, labeled data are heavily concentrated on a few ligases (e.g., CRBN and VHL), while the majority of E3 ligases remain underexplored yet are critical for expanding the design space of targeted degraders. Developing methods that enable robust cross-ligase generalization with minimal labeled data is therefore essential for improving the practical utility of computational PROTAC discovery. We reformulate PROTAC degradation activity prediction across E3 ligases as a few-shot meta-learning problem and present ProMeta, a prototype-based graph neural network trained through episodic meta-learning on source-E3 tasks and evaluated on held-out target-E3 tasks through support-conditioned inference. ProMeta performs inference without updating the encoder by dynamically estimating class prototypes from minimal target-ligase support samples. On the CRBN-to-VHL benchmark, ProMeta achieves AUROC values of 0.796 under K=2, Q=3 and 0.883 under K=2, Q=5, improving by 19.9% and 6.8%, respectively, over the corresponding supervised GNN baseline. Reverse VHL-to-CRBN transfer under the same protocol yielded AUROC values of 0.702 (K=2, Q=3) and 0.821 (K=2, Q=5), confirming bidirectional applicability while revealing direction and data-regime dependence. Together, these results support ProMeta as a practical framework for cross-ligase few-shot prediction under the evaluated support/query protocols.
ER -