Abstract
A novel series of pyrazolo[3,4-c]isoquinoline derivatives was discovered as B-Raf(V600E) inhibitors through scaffold hopping based on a literature lead PLX4720. Further SAR exploration and optimization led to the discovery of potent B-Raf(V600E) inhibitors with good oral bioavailability in rats and dogs. One of the compounds EBI-907 (13g) demonstrated excellent in vivo efficacy in B-Raf(V600E) dependent Colo-205 tumor xenograft models in mouse and is under preclinical studies for the treatment of melanoma and B-Raf(V600E) associated cancers.
Keywords:
B-Raf(V600E); Cancer; Kinase; Pyrazolo[3,4-c]isoquinoline; Scaffold hopping.
Copyright © 2015 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Animals
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Binding Sites
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Cell Line, Tumor
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Dogs
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Drug Evaluation, Preclinical
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Half-Life
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Humans
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Isoquinolines / chemistry
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Isoquinolines / pharmacokinetics
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Isoquinolines / therapeutic use
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Melanoma / drug therapy
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Mice
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Molecular Conformation
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Molecular Dynamics Simulation
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Protein Binding
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / therapeutic use
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Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
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Proto-Oncogene Proteins B-raf / metabolism
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Pyrazoles / chemistry
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Pyrazoles / pharmacokinetics
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Pyrazoles / therapeutic use
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Rats
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Structure-Activity Relationship
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Transplantation, Heterologous
Substances
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EBI-907
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Isoquinolines
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Protein Kinase Inhibitors
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Pyrazoles
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Proto-Oncogene Proteins B-raf
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isoquinoline