title: Synthesis and SAR studies of dual AKT/NF-κB inhibitors against melanoma.
abstract: 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.
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, 92037, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: Barile
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, 92037, USA.
authors.forename: Surya K
authors.initials: SK
authors.lastname: De
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, 92037, USA.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, 92037, USA.
authors.forename: Vida
authors.initials: V
authors.lastname: Chen
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, 92037, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, 92037, USA.
authors.forename: Ze'ev
authors.initials: Z
authors.lastname: Ronai
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, 92037, USA.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: C540767:3-(3-(1H-benzo(d)imidazol-2-yl)acryloyl)-6-chloro-4-phenylquinolin-2(1H)-one; D001562:Benzimidazoles; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT inhibitors; NF-κB inhibitors; cancer; drug discovery; melanoma