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Smyth, L.A.; Matthews, T.P.; Collins, I. |
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Bioorganic & medicinal chemistry |
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Binding Sites Computer Simulation Drug Design Humans Indoles/chemistry Protein Kinase Inhibitors/chemical synthesis/*chemistry/pharmacology Protein Kinases/*chemistry/metabolism Pyridones/chem |
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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. |
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Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, Belmont, Surrey SM2 5NG, UK. |
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refbase @ user @ |
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12903 |
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Author |
Smyth, L.A.; Matthews, T.P.; Collins, I. |
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Title |
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Type |
Journal Article |
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Year |
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Publication |
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Abbreviated Journal |
Bioorganic & medicinal chemistry |
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Volume |
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Issue |
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Pages |
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Keywords |
Binding Sites Computer Simulation Drug Design Humans Indoles/chemistry Protein Kinase Inhibitors/chemical synthesis/*chemistry/pharmacology Protein Kinases/*chemistry/metabolism Pyridones/chem |
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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. |
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Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, Belmont, Surrey SM2 5NG, UK. |
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refbase @ user @ |
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12942 |
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1978 |
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Crkva u svijetu |
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Split |
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13116 |
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1977 |
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Republièka konferencija SSRN BiH |
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Sarajevo |
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Proceedings Title: Socijalistièki savez radnog naroda Bosne i Hercegovine u ostvarivanju politike u odnosu na religiju i djelovanje vjerskih zajednica. Savjetovanje predsjednika opštinskih, Gradske i meðuopštinskih konferencija Socijalistièkog saveza radnog naroda Bosne i Hercegovine, Sarajevo, 1977 |
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13148 |
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1986 |
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Kršæanska sadašnjost. |
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Zagreb |
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Proceedings Title: Evangelizirati “sekulariziranu Evropu” : šesti simpozij evropskih biskupa, Rim, 7-11. listopada 1985 |
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refbase @ admin @ |
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13149 |
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