NU7441 reveals DNA-PK and BRD4 convergence as a therapeutic vulnerability in ovarian cancer

Vollständiger Abstract

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Abstract BRD4 and DNA-PK play critical roles in regulating DNA repair, genome integrity, and cellular growth and proliferation, highlighting their potential as targets for cancer therapy. BRD4 is upregulated in multiple cancers, including ovarian cancer, where its expression increases during tumor development and correlates with poorer overall and progression-free survival. In this study, we provide evidence that NU7441, traditionally classified as a selective DNA-PK inhibitor, also functions as a BRD4 inhibitor by directly displacing BRD4 from acetylated chromatin. Using a combination of in vitro and cell-based assays, we explored NU7441’s potential as a multi-target inhibitor that impairs both homologous recombination and non-homologous end joining. Combination studies revealed that NU7441 displays different sensitivity profiles compared to the single-target DNA-PK inhibitor AZD7648. By combining different cellular functions into a combined vulnerability in ovarian cancer, NU7441 offers a promising foundation for the development of next-generation multi-target inhibitors and biomarker-driven combination therapies. Together, these results provide a new lens through which to interpret previous NU7441 research and suggest that multi-target inhibition of BRD4 and DNA-PK can be leveraged to support new therapeutic strategies.