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

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

  • J Med Chem. 2009 Apr 23;52(8):2255-64. doi: 10.1021/jm801509w.
Dan Niculescu-Duvaz 1,  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
Affiliations

Affiliation

  • 1 Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.
PMID: 19323560 DOI: 10.1021/jm801509w
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.

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