PDF(Pubmed)
Abstract：
Aberrant activation of hedgehog (Hh) signaling has been implicated in various cancers. Current FDA-approved inhibitors target the seven-transmembrane receptor Smoothened, but resistance to these drugs has been observed. It has been proposed that a more promising strategy to target this pathway is at the GLI1 transcription factor level. GANT61 was the first small molecule identified to directly suppress GLI-mediated activity; however, its development as a potential anti-cancer agent has been hindered by its modest activity and aqueous chemical instability. Our study aimed to identify novel GLI1 inhibitors. JChem searches identified fifty-two compounds similar to GANT61 and its active metabolite, GANT61-D. We combined high-throughput cell-based assays and molecular docking to evaluate these analogs. Five of the fifty-two GANT61 analogs inhibited activity in Hh-responsive C3H10T1/2 and Gli-reporter NIH3T3 cellular assays without cytotoxicity. Two of the GANT61 analogs, BAS 07019774 and Z27610715, reduced Gli1 mRNA expression in C3H10T1/2 cells. Treatment with BAS 07019774 significantly reduced cell viability in Hh-dependent glioblastoma and lung cancer cell lines. Molecular docking indicated that BAS 07019774 is predicted to bind to the ZF4 region of GLI1, potentially interfering with its ability to bind DNA. Our findings show promise in developing more effective and potent GLI inhibitors.
摘要：
hedgehog（Hh）信号的异常激活与各种癌症有关。目前FDA批准的抑制剂靶向七种跨膜受体平滑，但是已经观察到对这些药物的抗性。已经提出，靶向该途径的更有希望的策略是在GLI1转录因子水平。GANT61是第一个被鉴定为直接抑制GLI介导的活性的小分子;然而，其适度的活性和水性化学不稳定性阻碍了其作为潜在抗癌剂的发展。我们的研究旨在鉴定新型GLI1抑制剂。JChem搜索确定了52种类似于GANT61及其活性代谢物的化合物，GANT61-D.我们结合高通量基于细胞的测定和分子对接来评估这些类似物。52种GANT61类似物中的5种抑制了Hh响应性C3H10T1/2和Gli-报道基因NIH3T3细胞测定中的活性，而没有细胞毒性。两种GANT61类似物,BAS07019774和Z27610715降低了C3H10T1/2细胞中Gli1mRNA的表达。用BAS07019774处理显著降低Hh依赖性成胶质细胞瘤和肺癌细胞系中的细胞活力。分子对接表明预测BAS07019774结合GLI1的ZF4区,潜在地干扰其结合DNA的能力。我们的发现显示了开发更有效和有效的GLI抑制剂的前景。
