胶质母细胞瘤 (GBM) 是一种预后不良的侵袭性脑癌。虽然手术切除是主要的治疗手段，但辅助治疗包括替莫唑胺 (TMZ) 化疗和放疗仅能稍微改善疾病进程和预后。不幸的是，大部分接受治疗的患者出现高度侵袭性、抗治疗的肿瘤的复发，并最终因病情恶化而死亡。为了增加化疗敏感性和克服治疗抵抗性，我们对 SWI/SNF染色质重塑复合物的BRG1和BRM催化亚单位的PFI-3溴域抑制剂进行了化学结构修饰。我们的修饰使得化合物使GBM 对DNA烷基化剂TMZ和辐射模拟物博来霉素敏感。我们通过GBM细胞系的细胞死亡ELISA和表位标记的BRG1或BRM溴域在GBM细胞中的细胞热稳定性检测筛选这些化学类似物。之后，我们鉴定了一种有效的类似物 IV-129，进一步修饰产生了具有独特性能的新一代溴域抑制剂。IV-255 和 IV-275 的生物活性比 IV-129 更高，其中 IV-255 选择性地结合 BRG1 的溴域而不结合 BRM，而IV-275 在BRG1和BRM的溴域上都能结合良好。相反，IV-191 既不结合 BRG1 的溴域也不结合 BRM 的溴域，也不改变 GBM 的化疗敏感性。重要的是，无论是 IV-255 还是 IV-275 都显著增加了通过核 γH2AX染色来确定的 TMZ 和博来霉素诱导的DNA损伤的程度。我们的结果证明，这些新一代抑制剂选择性地结合了 SWI/SNF复合物的催化亚单位的溴域，并使 GBM 对 TMZ 和博来霉素的抗癌效应产生敏感。这种方法有望改善 GBM 的治疗。 © 2023 The Authors. Journal of Cellular and Molecular Medicine 由细胞与分子医学基金会和John Wiley & Sons Ltd出版。

Glioblastoma (GBM) is an aggressive brain cancer with a poor prognosis. While surgical resection is the primary treatment, adjuvant temozolomide (TMZ) chemotherapy and radiotherapy only provide slight improvement in disease course and outcome. Unfortunately, most treated patients experience recurrence of highly aggressive, therapy-resistant tumours and eventually succumb to the disease. To increase chemosensitivity and overcome therapy resistance, we have modified the chemical structure of the PFI-3 bromodomain inhibitor of the BRG1 and BRM catalytic subunits of the SWI/SNF chromatin remodelling complex. Our modifications resulted in compounds that sensitized GBM to the DNA alkylating agent TMZ and the radiomimetic bleomycin. We screened these chemical analogues using a cell death ELISA with GBM cell lines and a cellular thermal shift assay using epitope tagged BRG1 or BRM bromodomains expressed in GBM cells. An active analogue, IV-129, was then identified and further modified, resulting in new generation of bromodomain inhibitors with distinct properties. IV-255 and IV-275 had higher bioactivity than IV-129, with IV-255 selectively binding to the bromodomain of BRG1 and not BRM, while IV-275 bound well to both BRG1 and BRM bromodomains. In contrast, IV-191 did not bind to either bromodomain or alter GBM chemosensitivity. Importantly, both IV-255 and IV-275 markedly increased the extent of DNA damage induced by TMZ and bleomycin as determined by nuclear γH2AX staining. Our results demonstrate that these next-generation inhibitors selectively bind to the bromodomains of catalytic subunits of the SWI/SNF complex and sensitize GBM to the anticancer effects of TMZ and bleomycin. This approach holds promise for improving the treatment of GBM.© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.