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.

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.

In this work, we designed and synthesized a series of novel BET PROTACs based on the clinical inhibitor ABBV-075. The favorable efficacy-safety balance of A10 underscores its strong potential as a preclinical candidate for AML therapy. This study highlights how rational PROTAC optimization can yield degraders with enhanced therapeutic windows, providing a promising path forward for targeted protein degradation in AML.

P1, N=140, Active, not recruiting, Incyte Corporation | Trial completion date: Dec 2026 --> Apr 2027 | Trial primary completion date: Dec 2025 --> Apr 2027

P1, N=66, Suspended, National Cancer Institute (NCI) | Trial completion date: Jan 2026 --> Sep 2028 | Recruiting --> Suspended | Trial primary completion date: Jan 2026 --> Sep 2028

P1, N=24, Not yet recruiting, Novartis Pharmaceuticals

The lead compound, 10k (ZX079), induces potent, dose- and time-dependent degradation of BRD4 and CBP and demonstrates superior suppression of oncogenic transcription and inhibition of AML cell proliferation compared with the dual BET/CBP inhibitor NEO2734. In vivo, 10k significantly reduces tumor growth in an AML xenograft model with TGI over 90%. Collectively, these findings highlight dual degradation of BRD4 and CBP as a promising strategy for AML.

Therapeutically, combined treatment with the BRD4 inhibitor JQ1 or the first bromodomain (BD1) selective inhibitor MS402 and an anti-GM-CSF antibody markedly suppressed TNBC progression and converted the tumor immune microenvironment from "cold" to "hot". In conclusion, our study reveals a previously unrecognized metabolic-epigenetic mechanism through which BRD4 drives GM-CSF-dependent TAMs activation and immune evasion in TNBC. Targeting BRD4 in combination with GM-CSF blockade represents a promising therapeutic strategy to overcome immune resistance in this aggressive breast cancer subtype.

Furthermore, CR10 significantly inhibited the growth of MV4-11 and A549 xenograft tumors at a dose as low as 2 mg/kg, without apparent toxicity. This semi-rigid linker-containing degrader represented a promising new mechanism-based candidate for the treatment of hematologic malignancies and lung cancer, warranting further investigation.

We constructed a multifunctional theranostic nanoplatform (PCN-CuS-JQ/RGD) based on an MRI-visible, Fe-porphyrin MOF (PCN(Fe)) carrier, decorated with CuS photothermal agents, a BRD4 inhibitor (JQ1), and a tumor-targeting peptide (RGD)...Crucially, in a bilateral tumor-bearing mouse model, our strategy demonstrated a powerful synergistic effect, significantly enhancing the efficacy of anti-PD-L1 immune checkpoint blockade therapy. This work presents a light-activatable degradation platform that achieves high tumor selectivity and potent immunotherapy, offering a promising new avenue for cancer treatment.

Immune suppression in T2D, and use of metformin, an activator of 5' Adenosine Monophosphate-activated Protein Kinase (AMPK), in such patients, prompted us to examine AMPK regulation of immune checkpoint expression. Chemical inhibition of AMPK with Compound C, and with the pan-BET inhibitor JQ1 or the BRD4-selective PROTAC inhibitor MZ-1, revealed that BET proteins regulate PD-1 and CTLA-4 through an AMPK-dependent pathway and TIM-3 and TIGIT through an AMPK-independent pathway. Personalized approaches to ICB treatment of TNBC patients with comorbid T2D should improve outcomes.

Both compounds displayed potent antiproliferative activity across multiple cancer cell lines, with higher potency than NEO2734, paclitaxel (PTX), and ARV-771. In a PC-3 xenograft mouse model, compound 29c achieved dose-dependent tumor growth inhibition (TGI) of up to 81.5% at a low dose of 0.2 mg/kg, administered every other day, significantly surpassing the efficacy of NEO2734 and PTX at higher doses. Together, 29c, a highly efficient CBP/p300 and BRD4 dual-target degrader, demonstrates significant therapeutic potential in prostate cancer and warrants further development.