Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF).

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.

• Authors: Dan Niculescu-Duvaz, Catherine Gaulon, Harmen P Dijkstra, Ion Niculescu-Duvaz, Alfonso Zambon, Delphine Ménard, Bart M J M Suijkerbuijk, Arnaud Nourry, Lawrence Davies, Helen Manne, Frank Friedlos, Lesley Ogilvie, Douglas Hedley, Steven Whittaker, Ruth Kirk, Adrian Gill, Richard D Taylor, Florence I Raynaud, Javier Moreno-Farre, Richard Marais, Caroline J Springer
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 52 Issue 8 Pg. 2255-64 (Apr 23 2009) ISSN: 1520-4804 [Electronic] United States
• PMID: 19323560 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Imidazoles
• Pyridines
• BRAF protein, human
• Proto-Oncogene Proteins B-raf

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacokinetics, pharmacology)
• Cell Line, Tumor
• Drug Screening Assays, Antitumor
• Female
• Humans
• Imidazoles (chemical synthesis, pharmacokinetics, pharmacology)
• In Vitro Techniques
• Melanoma, Experimental (metabolism)
• Mice
• Mice, Nude
• Microsomes, Liver (metabolism)
• Mutation
• Neoplasm Transplantation
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, genetics)
• Pyridines (chemical synthesis, pharmacokinetics, pharmacology)
• Structure-Activity Relationship
• Transplantation, Heterologous