Authors
Diyun Huang, Zeyu Shuang, Lu Chen, Hanyue Ouyang, Peiyu Yang, Lichang Huang, Wenchao Lu, Ming Shi, Xiaofan Ding, Baishan Jiang, Wenchao Wu
Published in
iScience. Volume 29. Issue 10. Pages 117600. Oct 16, 2026. Epub Sep 19, 2026.
Abstract
The discovery of molecular glue degraders (MGDs) is undergoing a paradigm shift from serendipitous discovery toward empirical design. However, efficiently prioritizing active leads from synthetic libraries while simultaneously confirming their E3 dependency remains a formidable challenge. In this study, we introduce the glue perturbation screening (GPS) platform, a conceptual and technical advance that integrates high-throughput, low-cost Digital RNA with pertUrbation of Genes 2 (DRUG-seq2) with isogenic cereblon (CRBN) wild-type/knockout (WT/KO) models. The significance of our work lies in the development of a multi-dimensional readout that digitizes compound activity and mechanism in a single step. By mapping transcriptomic perturbations onto a coordinate system of differential expression and gene set enrichment, we establish a tiered prioritization strategy: distinguishing high-potency glues from non-specific toxic molecules and recognizing latent biological activities in sub-threshold compounds that guide further structural optimization. This platform provides a scalable, mechanism-aware roadmap for the rational discovery of next-generation degraders, offering a powerful tool to accelerate the targeting of "undruggable" proteins.
PMID:
42824958
Bibliographic data and abstract were imported from PubMed on 02 Oct 2026.
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