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

Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]Apteridine 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. (C) 2016 Elsevier Ltd. All rights reserved.