Glioblastoma (GBM) is the most common primary brain malignancy, rarely amenable to treatment with a high recurrence rate. GBM are prone to develop resistance to the current repertoire of drugs, including the first-line chemotherapeutic agents with frequent recurrence, limiting therapeutic success. Recent clinical data has evidenced the BRD2 and BRD4 of the BET family proteins as the new druggable targets against GBM. In this relevance, we have discovered a compound (pyrano 1,3 oxazine derivative; NSC 328111; NS5) as an inhibitor of hBRD2 by the rational structure-based approach. The crystal structure of the complex, refined to 1.5 Å resolution, revealed that the NS5 ligand significantly binds to the N-terminal bromodomain (BD1) of BRD2 at the acetylated (Kac) histone binding site. The quantitative binding studies, by SPR and MST assay, indicate that NS5 binds to BD1 of BRD2 with a KD value of ∼1.3 µM. The cell-based assay, in the U87MG glioma cells, confirmed that the discovered compound NS5 significantly attenuated proliferation and migration. Furthermore, evaluation at the translational level established significant inhibition of BRD2 upon treatment with NS5. Hence, we propose that the novel lead compound NS5 has an inhibitory effect on BRD2 in glioblastoma.

中文翻译：

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基于吡喃1,3恶嗪的新型配体抑制胶质母细胞瘤的表观遗传阅读器hBRD2。

胶质母细胞瘤（GBM）是最常见的原发性脑恶性肿瘤，很少接受高复发率的治疗。GBM容易对目前的药物目录产生耐药性，包括经常复发的一线化疗药物，从而限制了治疗的成功。最近的临床数据已证明BET家族蛋白的BRD2和BRD4是对抗GBM的新药物靶标。与此相关，我们已经通过基于结构的合理方法发现了一种化合物（吡喃1,3恶嗪衍生物； NSC 328111； NS5）作为hBRD2抑制剂。精制至1.5Å分辨率的复合物的晶体结构表明，NS5配体在乙酰化（Kac）组蛋白结合位点与BRD2的N端溴结构域（BD1）显着结合。通过SPR和MST分析进行定量结合研究，表明NS5以约1.3 µM的KD值结合BRD2的BD1。在U87MG胶质瘤细胞中进行的基于细胞的测定证实，发现的化合物NS5显着减弱了增殖和迁移。此外，在NS5治疗后，在翻译水平上的评估建立了对BRD2的显着抑制。因此，我们提出了新型的前导化合物NS5对胶质母细胞瘤中的BRD2具有抑制作用。