Halofuginone is a Molecular Glue Degrader of Integrin β 4

ABSTRACT Integrin β 4 (gene name: ITGB4) overexpression is associated with aggressive phenotypes and poor prognosis across multiple solid tumors. Despite its clinical significance, therapeutic strategies targeting integrin β 4 remain underdeveloped. Targeted protein degradation technology, particularly molecular glue degraders, offer a promising approach for eliminating oncoproteins. However, the serendipitous discovery of molecular glues and limited exploration of substrate receptor have largely hindered the rational development of molecular glue degraders. In this study, through high throughput screening from a natural product library, we identified halofuginone (HF) as a potential molecular glue that promotes integrin β 4 degradation via the CRL4B ^WDR18 E3 ubiquitin ligase complex. HF administration markedly disrupted the aggressive progression of tumor cell both in vitro and in vivo. In summary, our study not only establishes HF as a promising degrader of integrin β 4 but also demonstrates the utility of natural product screening for discovering molecular glue degraders, providing a novel therapeutic strategy for targeting oncogenic transmembrane proteins.