dBET1

dBET1 is a potent and selective BRD4 protein degrader. The molecule, dubbed “degronimid”, is harnessed by combining two specific high affinity protein ligands, (+)-JQ1 for BRD4 and Phthalimide for E3 ubiquitin ligase cereblon (CRBN), tethered by a linker. Fully exploiting the cells’ own protein-degrading machinery, the molecule drags the ubiquitin ligase complex into the tagged protein, leading to a fast, sustainable, CRBN-dependent and ligand-guided BRD4 degradation. It is so selective that only three proteins, BRD2, 3, 4, of >7000 within the cell, were affected. dBET1 demonstrated powerful anti-leukemia activities both in cell and in animal model, with few noticeable side effects.