Novel Hinge Binder Improves Activity and Pharmacokinetic Properties of BRAF Inhibitors
| Autor: | Ion Niculescu-Duvaz, Alfonso Zambon, Natasha Preece, Delphine Menard, Lawrence Davies, Steven R. Whittaker, Lesley Ogilvie, Arnaud Nourry, Dan Niculescu-Duvaz, Bart M. J. M. Suijkerbuijk, Richard Marais, Filipa Lopes, Caroline J. Springer, Ruth Kirk, Helen A. Manne, Douglas Hedley |
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| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Oral Niacinamide Proto-Oncogene Proteins B-raf Pyridines Transplantation Heterologous Administration Oral Biological Availability Antineoplastic Agents Plasma protein binding Crystallography X-Ray Serine Mice Structure-Activity Relationship Models In vivo Drug Discovery Animals Humans Structure–activity relationship Threonine Inbred BALB C Mice Inbred BALB C Transplantation Heterologous Crystallography Kinase Chemistry Phenylurea Compounds Drug Discovery3003 Pharmaceutical Science Benzenesulfonates Imidazoles Molecular Hydrogen Bonding Sorafenib Biochemistry Pyrazines Administration X-Ray Molecular Medicine Female Neoplasm Transplantation Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry. 53:5639-5655 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm100383b |
| Popis: | Mutated BRAF serine/threonine kinase is implicated in several types of cancer, with particularly high frequency in melanoma and colorectal carcinoma. We recently reported on the development of BRAF inhibitors based on a tripartite A-B-C system featuring an imidazo[4,5]pyridin-2-one group hinge binder. Here we present the design, synthesis, and optimization of a new series of inhibitors with a different A-B-C system that has been modified by the introduction of a range of novel hinge binders (A ring). The optimization of the hinge binding moiety has enabled the development of compounds with low nanomolar potencies in both BRAF inhibition and cellular assays. These compounds display optimal pharmacokinetic properties that warrant further in vivo investigations. |
| Databáze: | OpenAIRE |
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