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.
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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