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. © 2009 American Chemical Society.
Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF) / Niculescu Duvaz, Dan; Gaulon, Catherine; Dijkstra, Harmen P.; Niculescu Duvaz, Ion; Zambon, Alfonso; Menard, Delphine; Suijkerbuijk, Bart M. J. M.; Nourry, Arnaud; Davies, Lawrence; Manne, Helen; Friedlos, Frank; Ogilvie, Lesley; Hedley, Douglas; Whittaker, Steven; Kirk, Ruth; Gill, Adrian; Taylor, Richard D.; Raynaud, Florence I.; Moreno Farre, Javier; Marais, Richard; Springer, Caroline J.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 52:8(2009), pp. 2255-2264. [10.1021/jm801509w]
Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF)
ZAMBON, Alfonso;
2009
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. © 2009 American Chemical Society.
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