Methionine aminopeptidase 2 (MetAp2) inhibition has been recognized as a promising approach for suppressing angiogenesis and cancer progression. Small molecule fumagillol derivatives with adamantane side groups were synthesized and evaluated for MetAp2 inhibition activity, and a lead molecule with superior abilities to inhibit the enzymatic activity of MetAp2 was identified. The compound, referred to as AD-3281, effectively suppressed proliferation of cancer and endothelial cells and impaired tube formation of endothelial cells in vitro. When administered systemically, AD-3281 was well tolerated and led to a significant suppression of human melanoma and mammary tumor xenografts grown in mice. The activity in vivo was associated with reduced angiogenesis and tumor proliferation as detected histologically. In order to develop a formulation that can solubilize AD-3281 with a minimal content of organic solvents, biodegradable nanoparticles comprised of poly-lactic-co-glycolic acid (PLGA) were fabricated and characterized. Compared with the free compound, AD-3281-loaded nanoparticles showed an advantageous cellular availability and uptake, leading to higher activity in cells and better transport in three-dimensional (3D) cultures. Taken together, we introduce a novel MetAp2 inhibitor with high anti-cancer activity and a stable nano-formulation with a high potential for future clinical translation.

Graphical abstract

中文翻译：

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新合成的甲硫氨酸氨肽酶2抑制剂阻碍肿瘤生长

甲硫氨酸氨基肽酶 2 (MetAp2) 抑制已被认为是抑制血管生成和癌症进展的有前途的方法。合成了具有金刚烷侧基的小分子烟曲霉醇衍生物，并评估了 MetAp2 抑制活性，并鉴定了具有优异抑制 MetAp2 酶活性能力的先导分子。该化合物称为 AD-3281，可有效抑制癌细胞和内皮细胞的增殖，并在体外抑制内皮细胞的管形成。全身给药时，AD-3281 耐受性良好，可显着抑制小鼠体内生长的人黑色素瘤和乳腺肿瘤异种移植物。如组织学检测到的，体内活性与减少的血管生成和肿瘤增殖有关。为了开发一种可以用最少的有机溶剂溶解 AD-3281 的制剂，我们制备并表征了由聚乳酸-乙醇酸共聚物 (PLGA) 组成的可生物降解纳米颗粒。与游离化合物相比，载有 AD-3281 的纳米粒子显示出有利的细胞可用性和摄取，从而导致细胞中的活性更高，并且在三维 (3D) 培养物中的运输更好。总之，我们介绍了一种具有高抗癌活性的新型 MetAp2 抑制剂和一种稳定的纳米制剂，具有很高的未来临床转化潜力。载有 AD-3281 的纳米颗粒显示出有利的细胞可用性和摄取，从而导致细胞中更高的活性和三维 (3D) 培养物中更好的运输。总之，我们介绍了一种具有高抗癌活性的新型 MetAp2 抑制剂和一种稳定的纳米制剂，具有很高的未来临床转化潜力。载有 AD-3281 的纳米颗粒显示出有利的细胞可用性和摄取，从而导致细胞中更高的活性和三维 (3D) 培养物中更好的运输。总之，我们介绍了一种具有高抗癌活性的新型 MetAp2 抑制剂和一种稳定的纳米制剂，具有很高的未来临床转化潜力。

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