Tumor-selective, chaperone-mediated protein degradation (CHAMP) of the bromodomain transcription factor BRD4

Background: The HSP90 chaperone complex has an important role in facilitating folding of newly synthesized substrate proteins, but can also mediate degradation of misfolded proteins through interaction with ubiquitin E3 ligases. Additionally, the HSP90 complex is often activated in cancer cells, which is associated with HSP90-binding agents displaying unusual tumor-selective pharmacokinetics in vivo. Taking advantage of these characteristics of the HSP90 chaperone complex, chaperone-mediated protein degraders (CHAMPs) are hetero-bifunctional small molecules that bind to a target protein of interest and direct its interaction with the HSP90 chaperone complex, thereby inducing degradation of the target protein via the ubiquitin proteasome system.