Novel tricyclic pyrazole BRAF inhibitors with imidazole or furan central scaffolds.
V-RAF murine sarcoma viral oncogene homolog B1 (BRAF) is a serine/threonine-specific protein kinase that is mutated with high frequency in cutaneous melanoma, and many other cancers. Inhibition of mutant BRAF is an attractive therapeutic approach for the treatment of melanoma. A triarylimidazole BRAF inhibitor bearing a phenylpyrazole group (dimethyl-[2-(4-{5-[4-(1H-pyrazol-3-yl)-phenyl]-4-pyridin-4-yl-1H-imidazol-2-yl}-phenoxy)-ethyl]-amine, 1a) was identified as an active BRAF inhibitor. Based on this starting point, we synthesized a series of analogues leading to the discovery of 6-{2-[4-(4-methyl-piperazin-1-yl)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-2,4-dihydro-indeno[1,2-c]pyrazole (1j), with nanomolar activity in three assays: inhibition of purified mutant BRAF activity in vitro; inhibition of oncogenic BRAF-driven extracellular regulated kinase (ERK) activation in BRAF mutant melanoma cell lines; and inhibition of proliferation in these cells.
Niculescu-Duvaz
Dan
D
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.
Niculescu-Duvaz
Ion
I
Suijkerbuijk
Bart M J M
BM
Ménard
Delphine
D
Zambon
Alfonso
A
Nourry
Arnaud
A
Davies
Lawrence
L
Manne
Helen A
HA
Friedlos
Frank
F
Ogilvie
Lesley
L
Hedley
Douglas
D
Takle
Andrew K
AK
Wilson
David M
DM
Pons
Jean-Francois
JF
Coulter
Tom
T
Kirk
Ruth
R
Cantarino
Neus
N
Whittaker
Steven
S
Marais
Richard
R
Springer
Caroline J
CJ
D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D005260:Female; D005663:Furans / Q000737:chemistry*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D051379:Mice; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
D005663:Furans; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C029899:imidazole; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C039281:furan