Targeted degradation of BRD4 by PROTACs: advances in cancer therapy

the ubiquitin-proteasome system (UPS). This review systematically summarizes developments over the past decade in BRD4-targeting PROTACs for cancer therapy, focusing on ternary complex design optimization, bioorthogonal activation strategies, and innovations in delivery systems. PROTACs facilitate BRD4 ubiquitination and degradation by simultaneously recruiting BRD4 and various E3 ligases, including CRBN, VHL, MDM2, and DCAF. By integrating BRD4 ligands (JQ1, ABBV-075, and HJB97) with strategies like macrocyclization, dual-targeting designs, and the dTAG system, potency and isoform selectivity have been enhanced. To minimize off-target toxicity, bioorthogonal activation strategies-such as photocaging and chemically induced approaches-have been developed, alongside precision delivery systems like antibody-PROTACs, folate-PROTACs, and stimuli-responsive PROTACs. The novel mechanism of molecular glue degraders is also explored. Multidimensional optimization is now propelling BRD4-PROTACs towards clinical translation, promising efficient, safe, and precisely controllable new strategies for cancer treatment.