title: Design and evaluation of 3-aminopyrazolopyridinone kinase inhibitors inspired by the natural product indirubin.
abstract: A lead-like kinase inhibitor screening library containing new 3-aminopyrazolopyridinones and closely related compounds was designed that contained hydrogen-bond donor-acceptor motifs and substitution vectors inspired by the natural product kinase inhibitor indirubin. The solubility of the 3-aminopyrazolopyridinone scaffold was more than 1000-fold greater than that of indirubin itself, and solubility was enhanced by reduction of the proportion of lipophilic aryl substituents or the introduction of basic groups. Several components of the library showed kinase inhibitory activity. A subset of diaryl-substituted analogues preferentially inhibited tyrosine kinases with low micromolar activity and good ligand efficiency, and showed cellular antiproliferative activity. The evaluation of the library shows that new, non-natural compounds with relevant biological activity and improved physicochemical properties can be generated from the natural product indirubin, providing compounds that may be useful for kinase inhibitor drug discovery.
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, Belmont, Surrey SM2 5NG, UK.
authors.forename: Lynette A
authors.initials: LA
authors.lastname: Smyth
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Matthews
authors.forename: Ian
authors.initials: I
authors.lastname: Collins
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011494:Protein Kinases; C027185:indirubin