Velcrins 是分子胶，通过诱导 RNase SLFN12 和磷酸二酯酶 PDE3A 之间形成蛋白质复合物来杀死细胞。该复合物的形成会激活 SLFN12，从而裂解 tRNALeu(TAA) 并诱导细胞凋亡。 Velcrins（例如临床研究化合物 BAY 2666605）被发现对癌细胞系百科全书中的多种实体瘤细胞系（包括胶质母细胞瘤细胞系）具有活性。因此，我们的目标是将 velcrins 描述为胶质母细胞瘤的新型治疗剂。在胶质母细胞瘤细胞系、癌症基因组图谱 (TCGA) 肿瘤样本和肿瘤神经球中测量了 PDE3A 和 SLFN12 表达水平。分析了 Velcrin 处理的细胞的活力、细胞凋亡诱导、细胞周期阶段和翻译的整体变化。获得细胞的转录谱。还监测了用 velcrin 治疗的异种移植小鼠的存活情况。我们鉴定了几种 velcrin 敏感的胶质母细胞瘤细胞系和 4 种 velcrin 敏感的胶质母细胞瘤患者衍生模型。我们确定 BAY 2666605 可以穿过血脑屏障，并在 GB1 细胞的原位异种移植模型中引起肿瘤完全消退。我们还确定 Velcrins BAY 2666605 和 BRD3800 在皮下胶质母细胞瘤 PDX 模型中诱导肿瘤消退。Velcrins 在胶质母细胞瘤临床前模型中具有抗肿瘤活性，值得作为潜在的治疗药物进行进一步研究。© 作者 2024。由牛津大学出版社出版、神经肿瘤学会和欧洲神经肿瘤学会。

Velcrins are molecular glues that kill cells by inducing the formation of a protein complex between the RNase SLFN12 and the phosphodiesterase PDE3A. Formation of the complex activates SLFN12, which cleaves tRNALeu(TAA) and induces apoptosis. Velcrins such as the clinical investigational compound, BAY 2666605, were found to have activity across multiple solid tumor cell lines from the cancer cell line encyclopedia, including glioblastoma cell lines. We therefore aim to characterize velcrins as novel therapeutic agents in glioblastoma.PDE3A and SLFN12 expression levels were measured in glioblastoma cell lines, the Cancer Genome Atlas (TCGA) tumor samples, and tumor neurospheres. Velcrin-treated cells were assayed for viability, induction of apoptosis, cell cycle phases, and global changes in translation. Transcriptional profiling of the cells was obtained. Xenograft-harboring mice treated with velcrins were also monitored for survival.We identified several velcrin-sensitive glioblastoma cell lines and 4 velcrin-sensitive glioblastoma patient-derived models. We determined that BAY 2666605 crosses the blood-brain barrier and elicits full tumor regression in an orthotopic xenograft model of GB1 cells. We also determined that the velcrins BAY 2666605 and BRD3800 induce tumor regression in subcutaneous glioblastoma PDX models.Velcrins have antitumor activity in preclinical models of glioblastoma, warranting further investigation as potential therapeutic agents.© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.