Synthesis and SAR studies of dual AKT/NF-κB inhibitors against melanoma

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. We describe SAR studies that led to compound 42 as a potent cellular inhibitor of phosphorylation of AKT1-3 and the NF-κB pathway in melanoma, breast, and prostate cell lines and showed remarkable efficacy in an in vivo melanoma xenograft model with the drug administered orally.