Discovery and optimization of N-acyl and N-aroylpyrazolines as B-Raf kinase inhibitors.
A high throughput screen identified N-aroylpyrazoline 1 as a selective inhibitor of the V600E mutant of B-Raf kinase. Parallel synthesis of acyl, aroyl, and sulfonyl derivatives led to the identification of several potent inhibitors in both enzymatic and cellular (pERK) assays such as compound 42.
Blackburn
Christopher
C
Millennium Pharmaceuticals Inc., 40 Landsdowne St., Cambridge MA 01239, United States. blackburn@mpi.com
Duffey
Matthew O
MO
Gould
Alexandra E
AE
Kulkarni
Bheemashankar
B
Liu
Jane X
JX
Menon
Saurabh
S
Nagayoshi
Masayuki
M
Vos
Tricia J
TJ
Williams
Juliet
J
D019943:Amino Acid Substitution; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011994:Recombinant Proteins; D048493:Proto-Oncogene Proteins B-raf