P2, N=88, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2026 --> Dec 2027

We tested these bifunctionals in a FKBP(F36V)-tagged transcription factor reporter system and found bifunctional induced transactivation is relatively common, being observed for bifunctionals with BET ligand JQ1, p300/CBP ligand GNE-781, CDK9 ligand SNS-032, and BRD9 ligand iBRD9. Together, these data establish bifunctionals targeting p300/CBP that toggle between a program of ultra-potent transactivation and repression depending on cellular context. Overall demonstrating that induced proximity with a given ligand does not encode a fixed functional outcome.

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.

Three genes (MXRA7, PLEKHG4B and ATP2B4) were identified to construct a SERG-related model in BLCA, which provides a basis for understanding BLCA pathogenesis and new insights into BLCA treatment.

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.

Activity screening identified derivative e24, which reduced tumor cell PD-L1 expression more effectively than positive control JQ-1, while the prototype nitidine had minimal effects. Critically, e24 specifically targets CSN5, an essential regulatory factor, to induce PD-L1 degradation, thereby blocking the PD-1/PD-L1 interaction between T cells and tumor cells and activating the tumor immune microenvironment. In Lewis tumor and MC38 mice models, e24 exerted antitumor effects by enhancing tumor-infiltrating T-cell immunity and inhibiting the activation of immunosuppressive MDSCs and Tregs.

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.

P2, N=13, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Nov 2026 --> Nov 2027 | Trial primary completion date: Nov 2026 --> Nov 2027

Notably, ICC with concurrent IDH1 mutations and MYC amplification exhibited sensitivity to the MYC inhibitor (+)-JQ1, but remained resistant to the IDH1 mutation inhibitor AG120. MYC overexpression conferred resistance to IDH1 mutation inhibitor, while creating a therapeutic vulnerability to MYC-targeted agents. The selective efficacy of (+)-JQ1 against IDH1-mutant ICC identified MYC inhibition as a promising precision medicine strategy for this molecular subset.

This study demonstrates that BET inhibition by JQ1 influences cellular sensitivity to TMZ and is associated with altered oxidative stress parameters and transcriptional reprogramming of epigenetic regulators in cervical cancer cells. While further protein-level and functional validation is required to establish causal mechanisms, these findings support the potential of BET-targeted strategies to modulate therapeutic responses in cervical cancer.

Consistent with these findings, RVX-208 treatment also reduced PD-1 levels in T cells from tumor bearing mice in vivo. Collectively, these results identify RVX-208 as a promising small-molecule immunotherapeutic agent for the treatment of lung cancer.

To investigate multimodal therapeutic approaches that combine epigenetic modulation with immunogenic and cytotoxic effects of oncolytic viruses (OVs), we evaluated two recombinant OVs, including the herpes simplex virus talimogene laherparepvec (T-VEC) and a measles vaccine virus (MeV-GFP), in combination with NEO2734 in four distinct NC cell lines. Evaluation of immunogenic cell death (ICD) markers displayed elevated ATP and HMGB1 levels and increased surface calreticulin with T-VEC and NEO2734 combinations. Overall, these findings indicate that combining OVs with BET/p300 inhibitors elicits potent antitumor responses, supports synergistic interactions and immunogenicity, and warrants further investigation in multimodal therapeutic strategies for NC.