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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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2017-10, Vol.27 (20), p.4730-4734
Hauptverfasser:	Barberis, Claude, Moorcroft, Neil, Arendt, Chris, Levit, Mikhail, Moreno-Mazza, Sandra, Batchelor, Joseph, Mechin, Ingrid, Majid, Tahir
Format:	Artikel
Sprache:	eng
Schlagworte:	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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Zusammenfassung:	[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