Development of novel, highly potent inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF): increasing cellular potency through optimization of a distal heteroaromatic group.
We describe the design, synthesis, and optimization of a series of new inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF), a kinase whose mutant form (V600E) is implicated in several types of cancer, with a particularly high frequency in melanoma. Our previously described inhibitors with a tripartite A-B-C system (where A is a hinge binding pyrido[4,5-b]imidazolone system, B is an aryl spacer group, and C is a heteroaromatic group) were potent against purified (V600E)BRAF in vitro but were less potent in accompanying cellular assays. Substitution of different aromatic heterocycles for the phenyl based C-ring is evaluated herein as a potential means of improving the cellular potencies of these inhibitors. Substituted pyrazoles, particularly 3-tert-butyl-1-aryl-1H-pyrazoles, increase the cellular potencies without detrimental effects on the potency on isolated (V600E)BRAF. Thus, compounds have been synthesized that inhibit, with low nanomolar concentrations, (V600E)BRAF, its downstream signaling in cells [as measured by the reduction of the phosphorylation of extracellular regulated kinase (ERK)], and the proliferation of mutant BRAF-dependent cells. Concomitant benefits are good oral bioavailability and high plasma concentrations in vivo.
Suijkerbuijk
Bart M J M
BM
The Institute of Cancer Research, Cancer Research UK Centre for Cancer Therapeutics, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.
Niculescu-Duvaz
Ion
I
Gaulon
Catherine
C
Dijkstra
Harmen P
HP
Niculescu-Duvaz
Dan
D
Ménard
Delphine
D
Zambon
Alfonso
A
Nourry
Arnaud
A
Davies
Lawrence
L
Manne
Helen A
HA
Friedlos
Frank
F
Ogilvie
Lesley M
LM
Hedley
Douglas
D
Lopes
Filipa
F
Preece
Natasha P U
NP
Moreno-Farre
Javier
J
Raynaud
Florence I
FI
Kirk
Ruth
R
Whittaker
Steven
S
Marais
Richard
R
Springer
Caroline J
CJ
D000818:Animals; D045744:Cell Line, Tumor; D015195:Drug Design; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D027384:Oncogene Proteins v-raf / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D009053:Sarcoma Viruses, Murine / Q000201:enzymology*; D017385:Sequence Homology; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D027384:Oncogene Proteins v-raf; D048493:Proto-Oncogene Proteins B-raf