Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, United States.
Department of Pathology and Laboratory Medicine, and Center for Cancer Research, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, United States.
Bioorg Med Chem. 2022 Jan 1;53:116533. doi: 10.1016/j.bmc.2021.116533. Epub 2021 Nov 27.
Glioblastoma (GBM) is the most aggressive and treatment-refractory malignant adult brain cancer. After standard of care therapy, the overall median survival for GBM is only ∼6 months with a 5-year survival <10%. Although some patients initially respond to the DNA alkylating agent temozolomide (TMZ), unfortunately most patients become resistant to therapy and brain tumors eventually recur. We previously found that knockout of BRG1 or treatment with PFI-3, a small molecule inhibitor of the BRG1 bromodomain, enhances sensitivity of GBM cells to temozolomide in vitro and in vivo GBM animal models. Those results demonstrated that the BRG1 catalytic subunit of the SWI/SNF chromatin remodeling complex appears to play a critical role in regulating TMZ-sensitivity. In the present study we designed and synthesized Structurally Related Analogs of PFI-3 (SRAPs) and tested their bioactivity in vitro. Among of the SRAPs, 9f and 11d show better efficacy than PFI-3 in sensitizing GBM cells to the antiproliferative and cell death inducing effects of temozolomide in vitro, as well as enhancing the inhibitor effect of temozolomide on the growth of subcutaneous GBM tumors.
胶质母细胞瘤（GBM）是最具侵袭性和治疗耐药性的成人脑癌。在标准治疗后，GBM 的总体中位生存期仅约 6 个月，5 年生存率<10%。尽管一些患者最初对 DNA 烷化剂替莫唑胺（TMZ）有反应，但不幸的是，大多数患者对治疗产生耐药性，脑肿瘤最终会复发。我们之前发现，BRG1 的敲除或 BRG1 溴结构域的小分子抑制剂 PFI-3 的治疗，增强了 GBM 细胞对 TMZ 的体外和体内 GBM 动物模型的敏感性。这些结果表明，SWI/SNF 染色质重塑复合物的 BRG1 催化亚基似乎在调节 TMZ 敏感性方面发挥着关键作用。在本研究中，我们设计并合成了 PFI-3 的结构相关类似物（SRAPs），并测试了它们在体外的生物活性。在这些 SRAPs 中，9f 和 11d 比 PFI-3 更有效地增强 GBM 细胞对 TMZ 的抗增殖和诱导细胞死亡作用的敏感性，以及增强 TMZ 对皮下 GBM 肿瘤生长的抑制作用。
