Sanford-Burnham Medical Research Institute, La Jolla, California, 92037, USA.
Chem Biol Drug Des. 2013 Nov;82(5):520-533. doi: 10.1111/cbdd.12177. Epub 2013 Sep 25.
The protein Kinase B alpha (AKT) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways are central regulators of cellular signaling events at the basis of tumor development and progression. Both pathways are often up-regulated in different tumor types including melanoma. We recently reported the identification of compound 1 (BI-69A11) as inhibitor of the AKT and the NF-κB pathways. Here, we describe SAR studies that led to novel fluorinated derivatives with increased cellular potency, reflected in efficient inhibition of AKT and IKKs. Selected compounds demonstrated effective toxicity on melanoma, breast, and prostate cell lines. Finally, a representative derivative showed promising efficacy in an in vivo melanoma xenograft model.
蛋白激酶 Bα（AKT）和核因子 kappa-轻链增强子的 B 细胞激活（NF-κB）通路是肿瘤发生和发展的基础上细胞信号事件的中央调控者。两条通路在不同的肿瘤类型中常常上调，包括黑色素瘤。我们最近报道了鉴定化合物 1（BI-69A11）作为 AKT 和 NF-κB 通路的抑制剂。在这里，我们描述了导致具有增加的细胞效力的新型氟化衍生物的 SAR 研究，这反映在 AKT 和 IKKs 的有效抑制上。所选化合物对黑色素瘤、乳腺和前列腺细胞系表现出有效的毒性。最后，代表性的衍生物在体内黑色素瘤异种移植模型中显示出有希望的疗效。
