Merck Healthcare, Merck KGaA , Frankfurter Str. 250 , 64293 Darmstadt , Germany.
Syngene International Limited , Biocon Park, Plot 2&3, Bommasandra-Jigani Link Road , 560 099 Bangalore , India.
J Med Chem. 2019 May 23;62(10):5025-5039. doi: 10.1021/acs.jmedchem.9b00041. Epub 2019 May 2.
Co- and post-translational processing are crucial maturation steps to generate functional proteins. MetAP-2 plays an important role in this process, and inhibition of its proteolytic activity has been shown to be important for angiogenesis and tumor growth, suggesting that small-molecule inhibitors of MetAP-2 may be promising options for the treatment of cancer. This work describes the discovery and structure-based hit optimization of a novel MetAP-2 inhibitory scaffold. Of critical importance, a cyclic tartronic diamide coordinates the MetAP-2 metal ion in the active site while additional side chains of the molecule were designed to occupy the lipophilic methionine side chain recognition pocket as well as the shallow cavity at the opening of the active site. The racemic screening hit from HTS campaign 11a was discovered with an enzymatic IC of 150 nM. The resynthesized eutomer confirmed this activity and inhibited HUVEC proliferation with an IC of 1.9 μM. Its structural analysis revealed a sophisticated interaction pattern of polar and lipophilic contacts that were used to improve cellular potency to an IC of 15 nM. In parallel, the molecular properties were optimized on plasma exposure and antitumor efficacy which led to the identification of advanced lead 21.
共翻译为中文 367 个字符，含标点符号 382 个。
翻译为中文后，标点符号不计入字符数。
协同和翻译后加工是生成功能性蛋白质的关键成熟步骤。MetAP-2 在这个过程中起着重要作用，其蛋白水解活性的抑制已被证明对血管生成和肿瘤生长很重要，这表明 MetAP-2 的小分子抑制剂可能是癌症治疗的有前途的选择。本工作描述了一种新型 MetAP-2 抑制骨架的发现和基于结构的命中优化。至关重要的是，环状酒石酸二酰胺在活性位点中与 MetAP-2 的金属离子配位，而分子的其他侧链被设计成占据疏水性蛋氨酸侧链识别口袋以及活性位点开口的浅腔。高内涵筛选命中物 11a 的 HTS 发现具有 150 nM 的酶 IC。重新合成的对映异构体证实了这一活性，并以 1.9 μM 的 IC 抑制 HUVEC 增殖。其结构分析揭示了复杂的极性和疏水性相互作用模式，用于提高细胞效力，达到 IC 的 15 nM。同时，对血浆暴露和抗肿瘤功效进行了分子性质优化，从而确定了先进的先导化合物 21。
