State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
Sci Rep. 2017 Feb 22;7:42860. doi: 10.1038/srep42860.
The hypoxia inducible factor (HIF) pathway has been considered to be an attractive anti-cancer target. One strategy to inhibit HIF activity is through the disruption of the HIF-1α-p300 protein-protein interaction. We report herein the identification of an osmium(II) complex as the first metal-based inhibitor of the HIF-1α-p300 interaction. We evaluated the effect of complex 1 on HIF-1α signaling pathway in vitro and in cellulo by using the dual luciferase reporter assay, co-immunoprecipitation assay, and immunoblot assay. Complex 1 exhibited a dose-dependent inhibition of HRE-driven luciferase activity, with an IC value of 1.22 μM. Complex 1 interfered with the HIF-1α-p300 interaction as revealed by a dose-dependent reduction of p300 co-precipitated with HIF-1α as the concentration of complex 1 was increased. Complex 1 repressed the phosphorylation of SRC, AKT and STAT3, and had no discernible effect on the activity of NF-κB. We anticipate that complex 1 could be utilized as a promising scaffold for the further development of more potent HIF-1α inhibitors for anti-cancer treatment.
缺氧诱导因子 (HIF) 途径已被认为是一种有吸引力的抗癌靶点。抑制 HIF 活性的一种策略是破坏 HIF-1α-p300 蛋白-蛋白相互作用。我们在此报告了一种锇 (II) 配合物作为第一个基于金属的 HIF-1α-p300 相互作用抑制剂的鉴定。我们通过双荧光素酶报告基因检测、共免疫沉淀检测和免疫印迹检测，在体外和细胞内评估了复合物 1 对 HIF-1α 信号通路的影响。复合物 1 表现出对 HRE 驱动的荧光素酶活性的剂量依赖性抑制，IC 值为 1.22 μM。复合物 1 干扰 HIF-1α-p300 相互作用，随着复合物 1 浓度的增加，与 HIF-1α 共沉淀的 p300 呈剂量依赖性减少。复合物 1 抑制 SRC、AKT 和 STAT3 的磷酸化，对 NF-κB 的活性没有明显影响。我们预计，复合物 1 可用作进一步开发更有效的 HIF-1α 抑制剂用于癌症治疗的有前途的支架。
