Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF).
Basic Information
ID: ALA1153434
Journal: J Med Chem
Title: Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF).
Authors: Niculescu-Duvaz D, Gaulon C, Dijkstra HP, Niculescu-Duvaz I, Zambon A, Ménard D, Suijkerbuijk BM, Nourry A, Davies L, Manne H, Friedlos F, Ogilvie L, Hedley D, Whittaker S, Kirk R, Gill A, Taylor RD, Raynaud FI, Moreno-Farre J, Marais R, Springer CJ.
Abstract: BRAF is a serine/threonine kinase that is mutated in a range of cancers, including 50-70% of melanomas, and has been validated as a therapeutic target. We have designed and synthesized mutant BRAF inhibitors containing pyridoimidazolone as a new hinge-binding scaffold. Compounds have been obtained which have low nanomolar potency for mutant BRAF (12 nM for compound 5i) and low micromolar cellular potency against a mutant BRAF melanoma cell line, WM266.4. The series benefits from very low metabolism, and pharmacokinetics (PK) that can be modulated by methylation of the NH groups of the imidazolone, resulting in compounds with fewer H-donors and a better PK profile. These compounds have great potential in the treatment of mutant BRAF melanomas.
CiteXplore: 19323560
DOI: 10.1021/jm801509w
Patent ID: ┄