Discovery of CDK4-selective molecular glue degraders by high-throughput proteomics
Zanon, P. R. A.; Shashikadze, B.; Winkler, D.; Scheller, I.; Bednarz, A.; Bartoschek, D.; Machata, S.; Graef, T.; Ohmayer, U.; Schwalb, B.; Steger, M.; Daub, H.
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Molecular glue degraders (MGDs) are proximity-inducing molecules that promote the destruction of disease-causing proteins by stabilizing novel interfaces between E3 ubiquitin ligases and target proteins. The rational design of MGDs remains exceptionally challenging, historically relying on serendipitous discoveries. Here, we deployed a high-throughput, mass spectrometry (MS)-based screen evaluating thousands of cereblon (CRBN)-directed compounds to expedite the identification of novel neosubstrates. This workflow led to the discovery of NE26394, a first-in-class MGD that selectively eliminates cyclin-dependent kinase 4 (CDK4), a critical oncogenic driver of cell cycle progression. Mechanistically, NE26394-induced CDK4 recognition by CRBN depends on the co-recruitment of endogenous INK4 family proteins. In CDK4-dependent cancer models, NE26394 effectively mimics the anti-proliferative RB-E2F pathway perturbations induced by clinical CDK4 inhibitors, rendering it an attractive candidate for further preclinical development.
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