Structure-based design and SAR development of 5,6-dihydroimidazolo[1,5-f]pteridine derivatives as novel Polo-like kinase-1 inhibitors

[Display omitted] Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2017-03, Vol.27 (5), p.1311-1315
Main Authors: Kiryanov, Andre, Natala, Srinivasa, Jones, Benjamin, McBride, Christopher, Feher, Victoria, Lam, Betty, Liu, Yan, Honda, Kouhei, Uchiyama, Noriko, Kawamoto, Tomohiro, Hikichi, Yuichi, Zhang, Lilly, Hosfield, David, Skene, Robert, Zou, Hua, Stafford, Jeffrey, Cao, Xiaodong, Ichikawa, Takashi
Format: Article
Language:English
Subjects:
Animals
Antitumor activity
Cell Cycle Proteins - antagonists & inhibitors
Drug Design
Enzyme Activation - drug effects
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Female
Heterografts
HT29 Cells
Humans
Imidazoles - chemical synthesis
Imidazoles - chemistry
Imidazoles - pharmacology
Mice
Molecular Structure
Multidrug resistance
PLK1 inhibitor
Polo-Like Kinase 1
Protein Serine-Threonine Kinases - antagonists & inhibitors
Proto-Oncogene Proteins - antagonists & inhibitors
Pteridines - chemical synthesis
Pteridines - chemistry
Pteridines - pharmacology
Structure-Activity Relationship
Structure-based drug design
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Summary:[Display omitted] Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2016.10.009