Research Unit Oncology, Merck Healthcare KGaA, the healthcare business of Merck KGaA, Darmstadt, Germany.
Discovery Technologies, Merck Healthcare KGaA, the healthcare business of Merck KGaA, Darmstadt, Germany.
Mol Cancer Ther. 2024 Feb 1;23(2):159-173. doi: 10.1158/1535-7163.MCT-23-0102.
N-terminal processing by methionine aminopeptidases (MetAP) is a crucial step in the maturation of proteins during protein biosynthesis. Small-molecule inhibitors of MetAP2 have antiangiogenic and antitumoral activity. Herein, we characterize the structurally novel MetAP2 inhibitor M8891. M8891 is a potent, selective, reversible small-molecule inhibitor blocking the growth of human endothelial cells and differentially inhibiting cancer cell growth. A CRISPR genome-wide screen identified the tumor suppressor p53 and MetAP1/MetAP2 as determinants of resistance and sensitivity to pharmacologic MetAP2 inhibition. A newly identified substrate of MetAP2, translation elongation factor 1-alpha-1 (EF1a-1), served as a pharmacodynamic biomarker to follow target inhibition in cell and mouse studies. Robust angiogenesis and tumor growth inhibition was observed with M8891 monotherapy. In combination with VEGF receptor inhibitors, tumor stasis and regression occurred in patient-derived xenograft renal cell carcinoma models, particularly those that were p53 wild-type, had Von Hippel-Landau gene (VHL) loss-of-function mutations, and a mid/high MetAP1/2 expression score.
N-端加工由蛋氨酸氨肽酶（MetAP）完成，这是蛋白质生物合成过程中蛋白质成熟的关键步骤。MetAP2 的小分子抑制剂具有抗血管生成和抗肿瘤活性。本文中，我们对结构新颖的 MetAP2 抑制剂 M8891 进行了表征。M8891 是一种有效的、选择性的、可逆的小分子抑制剂，能抑制人内皮细胞的生长，并能差异抑制癌细胞的生长。CRISPR 全基因组筛选鉴定出肿瘤抑制因子 p53 和 MetAP1/MetAP2 是对药物 MetAP2 抑制产生耐药性和敏感性的决定因素。MetAP2 的一种新鉴定的底物，翻译延伸因子 1-α-1（EF1a-1），可作为药效学生物标志物，用于细胞和小鼠研究中监测靶标抑制情况。M8891 单药治疗可观察到明显的血管生成和肿瘤生长抑制。与 VEGF 受体抑制剂联合使用，在患者来源的肾细胞癌异种移植模型中观察到肿瘤停滞和消退，特别是那些 p53 野生型、VHL 基因（VHL）功能丧失突变、MetAP1/2 表达评分中/高的模型。
