Targeted Delivery of Selective BET Inhibitors

Antibody-assisted delivery of chemotypes aims to address this, leading to several approved therapies; however, non-specific payload release and poor solid tumour penetration necessitate alternative approaches. To this end, we engineered a ligand-targeted drug conjugate, exploiting the over-expression of the prostate-specific membrane antigen (PSMA) in prostate cancer to selectively deliver and conditionally release RT53, a highly specific epigenetic inhibitor of the bromo and extra-terminal (BET) proteins.

RT53 phenocopies the effects of the well characterized IBET pan-BET inhibitor in vitro and in vivo, arresting cellular growth and downregulating solute carriers, while exhibiting antitumor activity in subcutaneous ectopic prostate cancer mouse models. Importantly, PSMA-targeted delivery and conditional release of RT53 achieves superior efficacy in vivo ameliorating on-target, off-tissue toxicity, and establishing proof-of-concept for the targeted delivery of small molecule epigenetic chemotherapeutics.