BRD3 (Bromodomain Containing 3)

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.

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.

PRAME is highly and frequently expressed in NUT carcinoma, and the most common oncoprotein causing NUT carcinoma, BRD4::NUTM1, contributes to these high PRAME levels. PRAME epitopes presented by HLA class I are a previously unrecognized therapeutic vulnerability for NUT carcinoma that warrants clinical trials testing PRAME-targeted immunotherapies in this neglected patient population.

Furthermore, histone deacetylases (HDACs) partially regulate the H3K18ac level following BRD3 degradation. Overall, we identified D072 as a specific degrader of BRD3 in the murine system that can inhibit proinflammatory microglia in autoimmune uveitis, potentially providing a therapeutic approach for uveitis.

By employing a set of conformationally restricted diamines as linkers between two BET-binding warheads, this work details the design and synthesis of two iterations of bivalent molecules. While finding the BET isoforms to be highly accommodating of bivalent molecules with diverse linker geometries, we present the discovery of 9h (GSK785), a bivalent inhibitor with an unprecedented BRD2/4-selective, BRD3 sparing profile.

Molecular testing identified a BRD3-NUTM1 fusion, confirming the diagnosis of NUT adnexal carcinoma. The patient remains disease-free at 1-year follow-up without further therapy.

These intrinsic dynamical differences influence the number and stability of accessible binding modes, with BRD3 showing greater plasticity and weaker binding, particularly for NSD3. Our findings support a model in which local sequence variation tunes conformational selection and induced fit mechanisms, offering a structural rationale for paralog-specific targeting of BET proteins.

This large single-center series confirms that HNNC exhibits marked morphological heterogeneity and poor prognosis. Accurate diagnosis relies on immunohistochemistry, with FISH and RNA sequencing as needed, offering molecular insights to guide prognosis and clinical management.

Most patients accepted different chemotherapy regimens (25/29), including paclitaxel albumin and platinum (13/25), etoposide and platinum (8/25). Metastasis can be recognized as the prognostic risk factor. Early detection of the cancer improves the chances of successful treatment, especially in patients with older age.

Furthermore, the inhibition of RAD51 was mainly observed in the cytoplasm, revealing a novel mechanism in which RAD51 forms a complex with GPX4 and FTH1 to synergistically regulate ROS production. These findings suggest that H3ac regulates BRD3 expression, promoting ROS accumulation through the RAD51-mediated ferroptosis signaling pathway, reversing radioresistance and enhancing radiosensitivity.

This case highlights the importance of recognizing NC in atypical locations and emphasizes the need for a thorough investigation in young patients with malignancies that display squamous differentiation. This report expands our understanding of biliary NC and underscores the challenges associated with its diagnosis and management.

Our study demonstrates that BRD4 epigenetically regulates the H19-mediated transcriptional control of adhesion molecules involved in collective migration and metastatic dissemination. Importantly, these effects are independent of AR status, suggesting that targeting the H19/BRD4 axis may represent a promising therapeutic avenue for advanced PCa.