Potent BRAF kinase inhibitors based on 2,4,5-trisubstituted imidazole with naphthyl and benzothiophene 4-substituents |
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| Authors: | Dan Niculescu-Duvaz Ion Niculescu-Duvaz Bart MJM Suijkerbuijk Delphine Ménard Alfonso Zambon Lawrence Davies Jean-Francois Pons Steven Whittaker Richard Marais Caroline J Springer |
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| Institution: | 1. The Institute of Cancer Research, Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom;2. The Institute of Cancer Research, Division of Cancer Biology, 237 Fulham Road, London SW3 6JB, United Kingdom;3. Evotec (UK) Ltd, 114 Milton Park, Abingdon, Oxfordshire, OX14 4SA, United Kingdom;4. The Paterson Institute for Cancer Research, The University of Manchester, Wilmslow Road, Manchester M20 4BX, United Kingdom |
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| Abstract: | The RAS–RAF–MEK–ERK pathway is hyperactivated in 30% of human cancers. BRAF is a serine–threonine kinase, belonging to this pathway that is mutated with high frequency in human melanoma and other cancers thus BRAF is an important therapeutic target in melanoma. We have designed inhibitors of BRAF based on 2,4,5-trisubstituted imidazoles with naphthyl and benzothiophene-4-substituents. Two compounds were discovered to be potent BRAF inhibitors: 1-(6-{2-4-(2-dimethylamino-ethoxy)phenyl]-5-(pyridin-4-yl)-1H-imidazol-4-yl} benzob]thiophen-3-yl)-2,2,2-trifluoroethanol (1i) with BRAF IC50 = 190 nM and with cellular GI50 = 2100 nM, and 6-{2-4-(2-dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-naphthalen-1-ol (1q) with IC50 = 9 nM and GI50 = 220 nM. |
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