Next-generation bromodomain inhibitors of the SWI/SNF complex enhance DNA damage and cell death in glioblastoma.
Next-generation bromodomain inhibitors of the SWI/SNF complex enhance DNA damage and cell death in glioblastoma.
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DOI：
10.1111/jcmm.17907
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发表时间：
2023-09
影响因子：
5.3
通讯作者：
Pfeffer, Lawrence M.
中科院分区：
文献类型：
--
作者：
Yang, Chuanhe;He, Yali;Wang, Yinan;McKinnon, Peter J.;Shahani, Vijay;Miller, Duane D.;Pfeffer, Lawrence M.
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方法，但辅助替莫唑胺（TMZ）化疗和放疗仅能轻微改善病程和结局。不幸的是，大多数接受治疗的患者会经历高度侵袭性、耐药性肿瘤的复发，并最终死于该疾病。为了增加化疗敏感性和克服治疗抗性，我们修饰了SWI/SNF染色质重塑复合物的BRG 1和BRM催化亚基的PFI-3布罗莫结构域抑制剂的化学结构。我们的修改导致的化合物，敏感GBM的DNA烷化剂TMZ和拟放射性博莱霉素。我们使用GBM细胞系的细胞死亡ELISA和使用GBM细胞中表达的表位标记的BRG 1或BRM溴结构域的细胞热位移测定来筛选这些化学类似物。然后鉴定并进一步修饰活性类似物IV-129，从而产生具有独特性质的新一代布罗莫结构域抑制剂。IV-255和IV-275具有比IV-129更高的生物活性，其中IV-255选择性地结合BRG 1的溴结构域而不是BRM，而IV-275与BRG 1和BRM溴结构域都很好地结合。相比之下，IV-191不结合布罗莫结构域或改变GBM化学敏感性。重要的是，IV-255和IV-275都显著增加了TMZ和博来霉素诱导的DNA损伤程度，如通过核γ H2 AX染色所确定的。我们的研究结果表明，这些下一代抑制剂选择性地结合SWI/SNF复合物的催化亚基的溴结构域，并使GBM对TMZ和博来霉素的抗癌作用敏感。这种方法有望改善GBM的治疗。
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.
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影响因子：
11.2
作者：
Picaud S;Da Costa D;Thanasopoulou A;Filippakopoulos P;Fish PV;Philpott M;Fedorov O;Brennan P;Bunnage ME;Owen DR;Bradner JE;Taniere P;O'Sullivan B;Müller S;Schwaller J;Stankovic T;Knapp S
通讯作者：
Knapp S
哺乳动物SWI/SNF复合物的蛋白质组学和生物信息学分析确定了在人类恶性肿瘤中的广泛作用。
影响因子：
30.8
作者：
Kadoch, Cigall;Hargreaves, Diana C.;Hodges, Courtney;Elias, Laura;Ho, Lena;Ranish, Jeff;Crabtree, Gerald R.
通讯作者：
Crabtree, Gerald R.
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
21.3
作者：
Huang, M;Qian, F;Wen, ZL
通讯作者：
Wen, ZL
影响因子：
14.9
作者：
Flanagan, JF;Peterson, CL
通讯作者：
Peterson, CL