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 anti-angiogenic 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 pharmacological 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 (RCC) 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.

中文翻译：

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新型蛋氨酸氨基肽酶 2 抑制剂 M8891 与 VEGF 受体抑制剂协同抑制肾细胞癌模型的肿瘤生长

甲硫氨酸氨肽酶 (MetAP) 的 N 末端加工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。在此，我们表征了结构新颖的 MetAP2 抑制剂 M8891。M8891 是一种有效的、选择性的、可逆的小分子抑制剂，可阻断人内皮细胞的生长，并差异性地抑制癌细胞的生长。CRISPR 全基因组筛选确定肿瘤抑制因子 p53 和 MetAP1/MetAP2 是对药物 MetAP2 抑制的耐药性和敏感性的决定因素。新鉴定的 MetAP2 底物翻译延伸因子 1-α-1 (EF1a-1) 可作为药效生物标志物，用于跟踪细胞和小鼠研究中的靶点抑制。M8891 单一疗法观察到强大的血管生成和肿瘤生长抑制作用。与 VEGF 受体抑制剂联合使用，患者来源的异种移植肾细胞癌 (RCC) 模型中出现肿瘤停滞和消退，特别是那些具有 Von Hippel-Landau 基因 (VHL) 功能丧失突变的 p53 野生型模型，和中/高 MetAP1/2 表达评分。