A novel B-RAF inhibitor blocks interleukin-8 (IL-8) synthesis in human melanoma xenografts, revealing IL-8 as a potential pharmacodynamic biomarker.
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.
Crawford
Shelby
S
Department of Immunology, Johnson & Johnson Pharmaceutical Research & Development LLC, La Jolla, CA 92121, USA.
Belajic
Daniel
D
Wei
Jianmei
J
Riley
Jason P
JP
Dunford
Paul J
PJ
Bembenek
Scott
S
Fourie
Anne
A
Edwards
James P
JP
Karlsson
Lars
L
Brunmark
Anders
A
Wolin
Ronald L
RL
Blevitt
Jonathan M
JM
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
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