title: A novel B-RAF inhibitor blocks interleukin-8 (IL-8) synthesis in human melanoma xenografts, revealing IL-8 as a potential pharmacodynamic biomarker.
abstract: B-RAF mutations have been identified in the majority of melanoma and a large fraction of colorectal and papillary thyroid carcinoma. Drug discovery efforts targeting mutated B-RAF have yielded several interesting molecules, and currently, three compounds are undergoing clinical evaluation. Inhibition of B-RAF in animal models leads to a slowing of tumor growth and, in some cases, tumor reduction. Described within is a novel series of diaryl imidazoles with potent, single-digit nanomolar, anti-B-RAF activity. One compound from this series has been detailed here and has been shown to block B-RAF(V600E)-dependent extracellular signal-regulated kinase 1/2 phosphorylation in SK-MEL-28 melanoma cells as well as soft agar colony formation and proliferation. Importantly, interleukin-8 (IL-8) was identified by quantitative real-time PCR and ELISA as a product of the elevated mitogen-activated protein kinase signaling in these cells. Plasma concentrations of IL-8 in mice bearing melanoma xenografts were significantly reduced following exposure to B-RAF inhibitors. Taken together, these data suggest that IL-8 could serve as a tractable clinical biomarker.
authors.affiliation: Department of Immunology, Johnson & Johnson Pharmaceutical Research & Development LLC, La Jolla, CA 92121, USA.
authors.forename: Shelby
authors.initials: S
authors.lastname: Crawford
authors.forename: Daniel
authors.initials: D
authors.lastname: Belajic
authors.forename: Jianmei
authors.initials: J
authors.lastname: Wei
authors.forename: Jason P
authors.initials: JP
authors.lastname: Riley
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dunford
authors.forename: Scott
authors.initials: S
authors.lastname: Bembenek
authors.forename: Anne
authors.initials: A
authors.lastname: Fourie
authors.forename: James P
authors.initials: JP
authors.lastname: Edwards
authors.forename: Lars
authors.initials: L
authors.lastname: Karlsson
authors.forename: Anders
authors.initials: A
authors.lastname: Brunmark
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Wolin
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Blevitt
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000235:genetics; D014183:Transplantation, Heterologous
chemical_list: D014408:Biomarkers, Tumor; D007093:Imidazoles; D016209:Interleukin-8; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf