Structure-based design and SAR development of 5, 6-dihydroimidazolo[1, 5-f]pteridine derivatives as novel Polo-like kinase-1 inhibitors. Issue 5 (1st March 2017)

• Record Type: Journal Article
• 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
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 5(2017)
• Page Start: 1311
• Page End: 1315
• Publication Date: 2017-03-01
• Subjects: PLK1 inhibitor -- Structure-based drug design -- Antitumor activity -- Multidrug resistance; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.10.009
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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. Compound1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model.