Discovery of N-substituted 7-azaindoles as PIM1 kinase inhibitors – Part I

[Display omitted] Novel N-substituted azaindoles have been discovered as PIM1 inhibitors. X-ray structures have played a significant role in orienting the chemistry effort in the initial phase of hit confirmation. Disclosure of an unconventional binding mode for 1 and 2, as demonstrated by X-ray cry...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2017-10, Vol.27 (20), p.4730-4734
Main Authors: Barberis, Claude, Moorcroft, Neil, Arendt, Chris, Levit, Mikhail, Moreno-Mazza, Sandra, Batchelor, Joseph, Mechin, Ingrid, Majid, Tahir
Format: Article
Language:English
Subjects:
Binding Sites
Cancer
Cell Line, Tumor
Cell Proliferation - drug effects
Crystallography, X-Ray
Drug Evaluation, Preclinical
Drug Screening Assays, Antitumor
Humans
Indoles - chemistry
Indoles - metabolism
Indoles - pharmacology
Inhibitors
Inhibitory Concentration 50
Molecular Dynamics Simulation
PIM1
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - metabolism
Protein Kinase Inhibitors - pharmacology
Protein Structure, Tertiary
Protein-Serine-Threonine Kinases - antagonists & inhibitors
Protein-Serine-Threonine Kinases - metabolism
Proto-Oncogene Proteins - antagonists & inhibitors
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors
Proto-Oncogene Proteins c-pim-1 - metabolism
Structure-Activity Relationship
X-ray crystallography
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Summary:[Display omitted] Novel N-substituted azaindoles have been discovered as PIM1 inhibitors. X-ray structures have played a significant role in orienting the chemistry effort in the initial phase of hit confirmation. Disclosure of an unconventional binding mode for 1 and 2, as demonstrated by X-ray crystallography, is presented and was an important factor in selecting and advancing a lead series.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2017.08.069