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 misfolded proteins through interaction with ubiquitin E3 ligases. Additionally, the is often activated cancer cells, which associated HSP90-binding agents displaying unusual tumor-selective pharmacokinetics vivo. Taking advantage these characteristics complex, chaperone-mediated protein degraders (CHAMPs) are hetero-bifunctional small molecules that bind to a target interest and direct its thereby inducing via proteasome system. BET bromodomain transcription factor BRD4 promising due regulating expression number cancer-associated genes, including MYC. In order chemically induce degradation, BRD4-CHAMP compound was by covalently coupling HSP90- BET-binding moieties short linker. Materials methods: CHAMPs were using standard medicinal chemistry techniques. CHAMP-induced biological activity studied vitro cell lines vivo tumor xenograft models. Results: vitro, treatment induced BRD4, leading growth inhibition apoptosis. could be immune-precipitated from CHAMP-treated LC-MS/MS proteomics detected multiple ligases complex. Consistent this, blocked inhibitor. Although displayed pan-BET binding selectivity biochemical assays, selectively degraded relative closely related family members, BRD2 BRD3, perhaps different protein-protein interactions HSP90. mouse models, consistent activation tumors, concentration tumors dramatically elevated plasma normal tissues for up 7 days following single dose. Treatment on once weekly dosing scheduled prolonged ∼90% resulting significant inhibition, depending model, regression. greater efficacy than clinical-stage inhibitor at tolerated doses, suggesting tumor-selective, BRD4-specific superior therapeutic index inhibition. Conclusions: Based findings, we have initiated Phase 1/2 clinical RNK05047 solid lymphoma patients. Conflict interest: Ownership: Stock Ranok Therapeutics