Research Progress on Antitumor Drugs Targeting BRD4

Bromodomain and extra-terminal structures (BET) family proteins serve as critical epigenetic “readers,” among which BRD4 can recognize and bind acetylated histones, recruit transcription elongation-related complexes, and maintain high-level expression of various proto-oncogenes and superenhancer-associated genes, playing a pivotal role in the development of malignant tumors. In recent years, small-molecule inhibitors and protein degraders (PROTACs) targeting BRD4 have advanced rapidly, evolving from early dual-bromodomain (BD1/BD2) pan-BET inhibitors to BD1/BD2 selective inhibitors, BRD4 selective degraders, antibody-PROTAC conjugates, and BRD4-related dual-target drugs, demonstrating promising antitumor potential. However, limitations such as limited monotherapy efficacy, dose-limiting toxicity, and acquired resistance continue to constrain their clinical translation. This article systematically reviews the tumor biology functions of BRD4 and the theoretical foundations of its drug targeting, focusing on representative compounds of BRD4-targeting inhibitors and degraders, their antitumor mechanisms, and preclinical/clinical research progress. It also discusses novel strategies including BD2 selective inhibition, dual-target inhibition, antibody-PROTAC conjugation, and nanodelivery systems, as well as resistance mechanisms and combination therapy approaches, aiming to provide insights for further optimization of BRD4-targeted epigenetic therapies.