BRD4 (Bromodomain Containing 4)

As a proof of concept, Hsp70TACs induced efficient degradation of intracellular Bromodomain Protein 4 (BRD4) via the ubiquitin-proteasome system (DC50 = 0.67 μM) and membrane-bound Programmed Death Ligand 1 (PD-L1) via caveolin-mediated endocytosis-lysosomal processing (DC50 = 0.84 μM). Moreover, Hsp70TACs exploits the elevated expression of Hsp70 in tumor cells to preferentially accumulate in these cells, thereby enabling the tumor-selective degradation of POIs in Hsp70-enriched tumor cells.

In this study, we designed a temperature-tunable photothermal immunotherapy hydrogel dressing (Pd/JQ1@SerMA) to overcome these melanoma postoperative complications...Notably, the hydrogel adaptively fills irregular wound defects, and accelerates postoperative tissue regeneration under mild photothermal stimulation (~ 42 °C). In conclusion, this temperature-tunable photothermal immunotherapeutic hydrogel exhibits remarkable clinical potential for preventing tumor recurrence, combating infection, and promoting wound healing.

In vitro and in vivo studies in CRPC models confirmed efficient BRD4 degradation, enhanced ferroptotic cell death, and superior antitumor efficacy with minimal systemic toxicity. Our findings position this nano-PROTAC strategy as a clinically promising dual-mechanism therapy capable of overcoming resistance in CRPC.

Further molecular mechanism study revealed that AZD5153 inhibited radiotherapy-activated ATM-chk1 pathway, suggesting that AZD5153 may enhance radiosensitivity by impairing DNA damage repair. Collectively, these results suggested that AZD5153 might be a promising radiosensitizing agent, and targeting the ATM-chk1 pathway may offer a novel therapeutic strategy to overcome radioresistance in pancreatic cancer.

When appended to the BET bromodomain inhibitor JQ1, this optimized handle yielded a potent and selective BRD4 degrader whose activity was dependent on RNF126. Importantly, transplantation of this handle onto a previously non-inhibitory ligand targeting the androgen receptor (AR) and its truncation variant, AR-V7, enabled selective degradation of both AR and AR-V7 in androgen-independent prostate cancer cells, thereby robustly inhibiting AR transcriptional activity beyond the established AR antagonist enzalutamide. Collectively, these findings demonstrate an optimized RNF126-based covalent handle for the rational development of molecular glue degraders against transcriptional regulators, including undruggable variants such as AR-V7.

Pharmacological BRD4 inhibition or epigenetic PML-SE repression alleviates liver inflammation and fibrosis. In conclusion, PML/BRD4-mediated SE activation via phase separation drives proinflammatory angiocrine signaling in LSECs, initiating the inflammatory cascade and subsequent immune cell recruitment during liver fibrosis.

The HBPROTAC system consists of two components: (1) Tz-PU, a tetrazine-conjugated HSP90 inhibitor designed for tumor-selective accumulation, and (2) TCO-caged PROTAC prodrugs (TCO-MZ1 or TCO-DT2216), which release active PROTACs (MZ1 or DT2216) through inverse electron demand Diels-Alder (IEDDA) reactions with Tz-PU...Moreover, inhibition by Tz-PU synergistically enhanced the degradation efficiency of the target proteins through HSP90-mediated signaling. The tumor-specific and enhanced degradation character of HBPROTAC was confirmed in various tumor cell lines and the melanoma mouse model, demonstrating that this strategy establishes a broadly applicable platform for tumor-specific spatiotemporal control of targeted protein degradation and diminished off-tissue on-target toxicity.

See also the graphical abstract(Fig. 1).

Standard treatment, consisting of surgical resection followed by radiotherapy and temozolomide chemotherapy, confers only limited therapeutic benefit, while a member of the bromodomain and extra-terminal (BET) family, BRD4, regulates transcriptional programs essential for oncogene activation, chromatin stability and glioma cell survival...Ongoing research continues to advance knowledge of its multifaceted functions. This review summarizes current knowledge on BRD4 in GBM, evaluates emerging BRD4-targeted therapeutic strategies and outlines major challenges and future directions for clinical translation.

Consequently, approximately 50% of the targeted cancer cells undergo apoptosis while nontarget cells retain more than 99% viability, underscoring the high selectivity of the SonoPIN system. Our study indicates that SonoPIN represents an innovative, noninvasive delivery platform for PROTAC therapeutics, offering a rapid and precise approach for targeted drug delivery in cancer treatment.

BET inhibition with (+)-JQ1 diminished FOXM1/MYC promoter occupancy at BRCA1 and RAD51, downregulated HR genes, and synergized with PARPi in viability and clonogenic assays. A BRD4 degrader (ZBC260) achieved potent BRD4 depletion at low nanomolar doses, suppressed FOXM1/MYC and HR gene expression, enhanced PARP1 trapping, and produced strong synergy with olaparib, including in patient-derived cancer cells. Clinically, BRD4 is highly expressed in ovarian cancer and independently predicts poor survival, outperforming FOXM1 and MYC. These data establish BRD4-directed disruption of the FOXM1-MYC axis as a strategy to induce "BRCAness" and broaden PARPi efficacy.

In vivo studies in a murine lung cancer model demonstrated potent suppression of primary, distant, and metastatic tumors. This study underscored the potential of nano-PROTACs to synergistically integrate protein-selective degradation, immunometabolic reprogramming, and photodynamic immunotherapy, offering a promising strategy for lung adenocarcinoma treatment.