Target-Driven Design of a Coumarinyl Chalcone Scaffold Based Novel EF2 Kinase Inhibitor Suppresses Breast Cancer Growth In Vivo.
Target-Driven Design of a Coumarinyl Chalcone Scaffold Based Novel EF2 Kinase Inhibitor Suppresses Breast Cancer Growth In Vivo.
复制标题
基于香豆素查尔酮支架的新型 EF2 激酶抑制剂的靶向驱动设计可抑制乳腺癌体内生长。
DOI：
10.1021/acsptsci.1c00030
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发表时间：
2021
影响因子：
--
通讯作者：
Ozpolat,Bulent
中科院分区：
文献类型：
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作者：
ComertOnder,Ferah;Kahraman,Nermin;BellurAtici,Esen;Cagir,Ali;Kandemir,Hakan;Tatar,Gizem;TaskinTok,Tugba;Kara,Goknur;Karliga,Bekir;Durdagi,Serdar;Ay,Mehmet;Ozpolat,Bulent
真核细胞延伸因子2激酶（eEF-2K）是一种不寻常的α激酶，通过延伸因子2（EF 2）的磷酸化参与蛋白质合成。eEF-2K在乳腺癌中高度过表达，其活性与显著缩短的患者生存期相关，并被证明是乳腺癌的潜在分子靶点。eEF-2K的晶体结构仍然未知，并且没有可用于临床应用的强效、安全和有效的抑制剂。我们设计并合成了几代潜在的抑制剂。通过构建与eEF-2K结构相似的肌球蛋白重链激酶A（myosin heavy-chain kinase A，MHCKA）的三维靶点模型，分析了抑制剂对eEF-2K结合口袋的影响。在高度侵袭性和侵入性的体外研究中（MDA-MB-436、MDA-MB-231和BT 20）和非侵袭性（MCF-7）乳腺癌细胞，我们发现了一种能高效抑制eEF的先导化合物在亚微摩尔浓度下的2K活性和在正常乳腺上皮细胞中通过诱导细胞凋亡抑制细胞增殖而无毒性。在裸鼠原位乳腺癌模型中，每周两次的单脂质基脂质体纳米颗粒显著抑制MDA-MB-231肿瘤的生长，没有观察到毒性。总之，我们的研究提供了一种高效和体内有效的新型小分子eEF-2K抑制剂，可用作乳腺癌或其他eEF-2K依赖性肿瘤的分子靶向治疗。
Eukaryotic elongation factor 2 kinase (eEF-2K) is an unusual alpha kinase involved in protein synthesis through phosphorylation of elongation factor 2 (EF2). eEF-2K is highly overexpressed in breast cancer, and its activity is associated with significantly shortened patient survival and proven to be a potential molecular target in breast cancer. The crystal structure of eEF-2K remains unknown, and there is no potent, safe, and effective inhibitor available for clinical applications. We designed and synthesized several generations of potential inhibitors. The effect of the inhibitors at the binding pocket of eEF-2K was analyzed after developing a 3D target model by using a domain of another α-kinase called myosin heavy-chain kinase A (MHCKA) that closely resembles eEF-2K.In silicostudies showed that compounds with a coumarin–chalcone core have high predicted binding affinities for eEF-2K. Usingin vitrostudies in highly aggressive and invasive (MDA-MB-436, MDA-MB-231, and BT20) and noninvazive (MCF-7) breast cancer cells, we identified a lead compound that was highly effective in inhibiting eEF-2K activity at submicromolar concentrations and at inhibiting cell proliferation by induction of apoptosis with no toxicity in normal breast epithelial cells.In vivosystemic administration of the lead compound encapsulated in single lipid-based liposomal nanoparticles twice a week significantly suppressed growth of MDA-MB-231 tumors in orthotopic breast cancer models in nude mice with no observed toxicity. In conclusion, our study provides a highly potent andin vivoeffective novel small-molecule eEF-2K inhibitor that may be used as a molecularly targeted therapy breast cancer or other eEF-2K-dependent tumors.