设计并合成靶向 Arf1 的 γ-二肽作为头颈部鳞状细胞癌潜在治疗药物。
Design and Synthesis of Arf1-Targeting γ-Dipeptides as Potential Agents against Head and Neck Squamous Cell Carcinoma.
机构信息
Institut des Biomolécules Max Mousseron, UMR 5247, CNRS-UM-ENSCM, UFR des Sciences Pharmaceutiques et Biologiques, 15 avenue Charles Flahault, 34093 Montpellier Cedex 5, France.
Department of Oral Biology and Diagnostic Sciences, Georgia Cancer Center, Augusta University, 1120 15th Street, Augusta, GA 309212, USA.
出版信息
Cells. 2020 Jan 24;9(2):286. doi: 10.3390/cells9020286.
BACKGROUND
Head and neck squamous cell carcinoma (HNSCC) is one of the leading causes of cancer-related deaths and calls for new druggable targets. We have previously highlighted the critical role of ADP-ribosylation factor-1 (Arf1) activation in HNSCC. In the present study, we address the question whether targeting Arf1 could be proposed as a valuable strategy against HNSCC.
METHODS
We rationally designed and synthesized constrained ATC-based (4-amino-(methyl)-1,3-thiazole-5-carboxylic acid) γ-dipeptides to block Arf1 activation. We evaluated the effects of these γ-dipeptides in HNSCC cells: The cell viability was determined in 2D and 3D cell cultures after 72 h treatment and Arf1 protein levels and activity were assessed by GGA3 pull-down and Western blotting assays.
RESULTS
Targeting Arf1 offers a valuable strategy to counter HNSCC. Our new Arf1-targeting compounds revealed a strong in vitro cytotoxicity against HNSCC cells, through inhibiting Arf1 activation and its downstream pathways.
CONCLUSIONS
Arf1-targeting γ-dipeptides developed in this study may represent a promising targeted therapeutic to improve managing the HNSCC disease.
背景
头颈部鳞状细胞癌（HNSCC）是癌症相关死亡的主要原因之一，需要新的可用药靶。我们之前强调了 ADP-核糖基化因子-1（Arf1）激活在 HNSCC 中的关键作用。在本研究中，我们探讨了针对 Arf1 是否可以作为一种有价值的 HNSCC 治疗策略。
方法
我们合理设计并合成了基于 ATC 的约束（4-氨基-（甲基）-1,3-噻唑-5-羧酸）γ-二肽，以阻断 Arf1 的激活。我们在 HNSCC 细胞中评估了这些γ-二肽的作用：在 72 h 处理后通过二维和三维细胞培养测定细胞活力，并通过 GGA3 下拉和 Western blot 测定评估 Arf1 蛋白水平和活性。
结果
针对 Arf1 为治疗 HNSCC 提供了有价值的策略。我们新的针对 Arf1 的化合物通过抑制 Arf1 的激活及其下游途径，对 HNSCC 细胞表现出很强的体外细胞毒性。
结论
本研究开发的针对 Arf1 的γ-二肽可能代表一种有前途的靶向治疗方法，可改善 HNSCC 疾病的管理。
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