JQ-1

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.

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.

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.

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.

We designed and synthesized SKP2-recruiting degraders by linking SL1 to the BRD4 inhibitor JQ1...We further demonstrate that SKP2-directed PROTACs effectively degrade Androgen receptor (AR) in 22RV1 cells. These findings emphasize that SKP2, frequently overexpressed in various tumor cells, can be successfully exploited for TPD through non-covalent PROTACs, expanding the pool of E3 ligases available for potential therapeutic applications.

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. 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.

HB023 successfully addresses the challenge of glutamine deprivation-induced immune escape by integrating metabolic inhibition with immune checkpoint blockade. This dual-modulatory approach reprograms the tumor immune microenvironment and improves immunotherapeutic efficacy, representing a promising strategy for advancing cancer treatment.

Here, we report that combining the BET inhibitor JQ1 with the autophagy inhibitor chloroquine (CQ) synergistically amplifies ERS, leading to enhanced ICD in OSCC models. This minimally invasive platform ensures sustained drug release, improves tumor accumulation, and minimizes systemic exposure. Our study not only elucidates a druggable autophagy-ERS-ICD axis but also provides a versatile transdermal delivery strategy with potential applicability to a range of solid tumors.

Furthermore, our findings show that the dual-targeting agents JQ-1 and CX-6258-focused on FOSL1/AP-1 and PIM kinases, respectively-effectively suppress both the progenitor properties and the growth of mouse and human DNPC surrogates in vitro and in vivo. Thus, early eradication of castration-tolerant Club-like cells presents a promising therapeutic strategy to mitigate prostate cancer progression toward CRPC.