Synthesis and SAR Studies of Dual AKT/NF‐κB Inhibitors Against Melanoma. (25th September 2013)

• Record Type: Journal Article
• Authors: Barile, Elisa; De, Surya K.; Feng, Yongmei; Chen, Vida; Yang, Li; Ronai, Ze'ev; Pellecchia, Maurizio
• Is Part Of: Chemical biology & drug design. Volume 82:Number 5(2013:Nov.)
• Page Start: 520
• Page End: 533
• Publication Date: 2013-09-25
• Subjects: Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12177
• Languages: English
• ISSNs: 1747-0277

Abstract

<abstract abstract-type="main" id="cbdd12177-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 <bold>1</bold> (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 <italic>in vivo</italic> melanoma xenograft model.</p> </abstract>