Structural studies furthered our understanding of compound activity, with high-resolution x-ray cocrystal structures revealing an unexpected interaction between the E3 ligase recruiting ligand, thalidomide, and Trp81 on BRD4 BD1, resulting from the tryptophan side chain flipping in its relative orientation and effectively sequestering thalidomide, thereby preventing its binding to CRBN and abrogating Degrader activity. Such "Degrader collapse" might be a hitherto under-represented mechanism for lack of action in prototypical Degrader design and may merit re-investigation of past failures or prompt structural evaluation of binary complexes in future cases where the experimental results fail to align with biochemical binding results.