A Novel, Selective, and Efficacious Nanomolar Pyridopyrazinone Inhibitor of V600EBRAF
Autor: | Steven R. Whittaker, Helen A. Manne, Ruth S. Kirk, Alfonso Zambon, Richard Marais, Delphine Menard, Lesley Ogilvie, Douglas Hedley, Jorge S. Reis-Filho, Natasha Preece, Maryou B K Lambros, Filipa Lopes, Caroline J. Springer, Sareena Rana |
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Rok vydání: | 2010 |
Předmět: |
Models
Molecular Cancer Research endocrine system diseases Administration Oral Mice Models Mutant protein Enzyme Inhibitors Phosphorylation Extracellular Signal-Regulated MAP Kinases skin and connective tissue diseases Melanoma Inbred BALB C Mice Inbred BALB C Heterologous Tumor Kinase Nucleic Acid Hybridization Neoplasm Proteins Oncology Administration Colonic Neoplasms Female Signal transduction Cell Division Oral Proto-Oncogene Proteins B-raf Cell Survival Transplantation Heterologous Breast Neoplasms Enzyme-Linked Immunosorbent Assay Amino Acid Substitution Animals Cell Line Tumor Humans Biology Article Cell Line In vivo medicine neoplasms Transplantation Molecular Cancer medicine.disease digestive system diseases enzymes and coenzymes (carbohydrates) Cancer cell Cancer research V600E |
Zdroj: | Cancer Research. 70:8036-8044 |
ISSN: | 1538-7445 0008-5472 |
DOI: | 10.1158/0008-5472.can-10-1366 |
Popis: | 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, V600EBRAF. 1t inhibits signaling downstream of V600EBRAF 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 V600EBRAF-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. Cancer Res; 70(20); 8036–44. ©2010 AACR. |
Databáze: | OpenAIRE |
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