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Synthesis and SAR Studies of Dual AKT / NF ‐κ B Inhibitors Against Melanoma
Author(s) -
Barile Elisa,
De Surya K.,
Feng Yongmei,
Chen Vida,
Yang Li,
Ronai Ze'ev,
Pellecchia Maurizio
Publication year - 2013
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12177
Subject(s) - protein kinase b , melanoma , in vivo , chemistry , cancer research , pi3k/akt/mtor pathway , signal transduction , biology , biochemistry , microbiology and biotechnology
The protein K inase B alpha ( AKT ) and nuclear factor kappa‐light‐chain‐enhancer of activated B cells ( NF ‐κ B ) 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 IKK s. 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.