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

Abstract

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.

• Authors: Andre Kiryanov, Srinivasa Natala, Benjamin Jones, Christopher McBride, Victoria Feher, Betty Lam, Yan Liu, Kouhei Honda, Noriko Uchiyama, Tomohiro Kawamoto, Yuichi Hikichi, Lilly Zhang, David Hosfield, Robert Skene, Hua Zou, Jeffrey Stafford, Xiaodong Cao, Takashi Ichikawa
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 27 Issue 5 Pg. 1311-1315 (03 01 2017) ISSN: 1464-3405 [Electronic] England
• PMID: 28169164 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• Cell Cycle Proteins
• Enzyme Inhibitors
• Imidazoles
• Proto-Oncogene Proteins
• Pteridines
• imidazolone
• Protein Serine-Threonine Kinases

Topics

• Animals
• Cell Cycle Proteins (antagonists & inhibitors)
• Drug Design
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Female
• HT29 Cells
• Heterografts
• Humans
• Imidazoles (chemical synthesis, chemistry, pharmacology)
• Mice
• Molecular Structure
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Proto-Oncogene Proteins (antagonists & inhibitors)
• Pteridines (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Polo-Like Kinase 1