title: A novel, selective, and efficacious nanomolar pyridopyrazinone inhibitor of V600EBRAF.
abstract: Oncogenic BRAF is a critical driver of proliferation and survival and is thus a validated therapeutic target in cancer. We have developed a potent inhibitor, termed 1t (CCT239065), of the mutant protein kinase, (V600E)BRAF. 1t inhibits signaling downstream of (V600E)BRAF in cancer cells, blocking DNA synthesis, and inhibiting proliferation. Importantly, we show that 1t is considerably more selective for mutated BRAF cancer cell lines compared with wild-type BRAF lines. The inhibitor is well tolerated in mice and exhibits excellent oral bioavailability (F = 71%). Suppression of (V600E)BRAF-mediated signaling in human tumor xenografts was observed following oral administration of a single dose of 1t. As expected, the growth rate in vivo of a wild-type BRAF human tumor xenograft model is unaffected by inhibitor 1t. In contrast, 1t elicits significant therapeutic responses in mutant BRAF-driven human melanoma xenografts.
authors.affiliation: Signal Transduction Team, Section of Cell and Molecular Biology, Molecular Pathology Team, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Steven
authors.initials: S
authors.lastname: Whittaker
authors.forename: Delphine
authors.initials: D
authors.lastname: Ménard
authors.forename: Ruth
authors.initials: R
authors.lastname: Kirk
authors.forename: Lesley
authors.initials: L
authors.lastname: Ogilvie
authors.forename: Douglas
authors.initials: D
authors.lastname: Hedley
authors.forename: Alfonso
authors.initials: A
authors.lastname: Zambon
authors.forename: Filipa
authors.initials: F
authors.lastname: Lopes
authors.forename: Natasha
authors.initials: N
authors.lastname: Preece
authors.forename: Helen
authors.initials: H
authors.lastname: Manne
authors.forename: Sareena
authors.initials: S
authors.lastname: Rana
authors.forename: Maryou
authors.initials: M
authors.lastname: Lambros
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Springer
mesh_terms: D000284:Administration, Oral; D019943:Amino Acid Substitution; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000235:genetics*; D009693:Nucleic Acid Hybridization; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D014183:Transplantation, Heterologous
chemical_list: D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases
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