Abstract：
Glioblastoma (GBM) is a highly aggressive and treatment-resistant brain tumor, necessitating novel therapeutic strategies. In this study, we present a mechanistic breakthrough by designing and evaluating a series of abiraterone-installed hydroxamic acids as potential dual inhibitors of CYP17A1 and HDAC6 for GBM treatment. We established the correlation of CYP17A1/HDAC6 overexpression with tumor recurrence and temozolomide resistance in GBM patients. Compound 12, a dual inhibitor, demonstrated significant anti-GBM activity in vitro, particularly against TMZ-resistant cell lines. Mechanistically, compound 12 induced apoptosis, suppressed recurrence-associated genes, induced oxidative stress and initiated DNA damage response. Furthermore, molecular modeling studies confirmed its potent inhibitory activity against CYP17A1 and HDAC6. In vivo studies revealed that compound 12 effectively suppressed tumor growth in xenograft and orthotopic mouse models without inducing significant adverse effects. These findings highlight the potential of dual CYP17A1 and HDAC6 inhibition as a promising strategy for overcoming treatment resistance in GBM and offer new hope for improved therapeutic outcomes.
摘要：
胶质母细胞瘤（GBM）是一种高度侵袭性和耐药性的脑肿瘤，需要新的治疗策略。在这项研究中,我们通过设计和评估一系列阿比曲酮安装的异羟肟酸作为CYP17A1和HDAC6治疗GBM的潜在双重抑制剂,提出了一个机理上的突破.我们建立了GBM患者CYP17A1/HDAC6过表达与肿瘤复发和替莫唑胺耐药的相关性。化合物12，双重抑制剂，在体外表现出显著的抗GBM活性，特别是针对TMZ抗性细胞系。机械上,化合物12诱导细胞凋亡，抑制复发相关基因，诱导氧化应激并引发DNA损伤反应。此外，分子建模研究证实了其对CYP17A1和HDAC6的有效抑制活性。体内研究显示,化合物12有效抑制异种移植和原位小鼠模型中的肿瘤生长,而不诱导显著的副作用。这些发现强调了CYP17A1和HDAC6双重抑制作为克服GBM治疗耐药性的有希望的策略的潜力，并为改善治疗结果提供了新的希望。
