Abstract
N-Substituted azaindoles have been discovered as pan-PIM kinase inhibitors. Initial SAR, early ADME and PK/PD data of a series of compounds is described and led to the identification of promising pan-PIM inhibitors which validated our interest in the 7-azaindole scaffold and led us to pursue the identification of a clinical candidate.
Keywords:
AML; Cancer; Hit-to-Lead; PK/PD; Pan-PIM kinases; Small molecule inhibitor; X-ray crystallography.
Copyright © 2017 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Crystallography, X-Ray
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Drug Evaluation, Preclinical
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Enzyme Activation / drug effects
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Half-Life
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Humans
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Indoles / chemistry*
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Indoles / metabolism
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Indoles / pharmacology*
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Inhibitory Concentration 50
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Mice
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Microsomes, Liver / drug effects
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Microsomes, Liver / metabolism
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins c-pim-1 / chemistry
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Proto-Oncogene Proteins c-pim-1 / metabolism*
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Rats
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Structure-Activity Relationship
Substances
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7-azaindole dimer
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Indoles
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-pim-1
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proto-oncogene proteins pim