We can therefore rationalize the similar BRD4 binding affinities for phenolic ether Degrader 14 and BDO1A383 (2.4 µM and 1.8 µM, respectively). The piperazine-based Degrader 34, however, adopted a surprising binding mode in the co-crystal structure. There was excellent electron density for the entire Degrader molecule in this example, and the thalidomide moiety was found to fold back onto the protein, packing against the side chain of Trp81, which had flipped relative to its orientation in the complex with BDO1A383 and the thalidomide-free parent molecule 29 (Figure ). Also, the central benzimidazole ring of 34 was rotated by about 180 degrees and was slightly tilted compared with the orientation seen in the other complexes with this core scaffold (Figure ). This orientation of 34 was also stabilized via an interesting intramolecular interaction of the thalidomide piperidine-2,6-dione with the aromatic ring of the phenol ether moiety of the inhibitor. The packing of the thalidomide moiety against the Trp81 side chain is likely to contribute to the overall activity observed for this compound against BRD4 (Table ) but could also rationalize the lack of ability to induce ubiquitination (Figure ), since the thalidomide binding moiety is sequestered by BRD4 BD1 Trp81 and therefore not freely available for binding to form a ternary complex. The 'collapse' of Degraders leading to E3 ligase ligandtarget protein binding interactions has also been observed for VHL-recruiting Degraders and may represent an under-reported mechanism by which some putative Degrader molecules are inactive with respect to target protein degradation. Degrader 34 displayed a nanomolar (65 nM) activity against BRD4 BD1, similar to (+)-JQ1, and this prompted us to compare the binding poses of both. Indeed, 34 mimics (+)-JQ1 by flipping Trp81 and interacting with it; the packing against Trp81, however, occurs from two different sides of the indole ring (Figure , D and Supporting Figure ). The crystal structure of the complex with 34 also showed an interesting stacking interaction of thalidomide moieties from symmetry-related molecules (Supporting Figure ).