Identification of new 4-N-substituted 6-aryl-7H-pyrrolo[2,3-d]pyrimidine-4-amines as highly potent EGFR-TK inhibitors with Src-family activity
| Autor: | Eli Kjøbli, Eirik Sundby, Svein Jacob Kaspersen, Geir Bjørkøy, Line Rydså, Steffen Bugge, Jin Han, Bård Helge Hoff, Kristin G. Nørsett |
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| Rok vydání: | 2014 |
| Předmět: |
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Molecular Pharmaceutical Science Antineoplastic Agents Pharmacology Colony stimulating factor 1 receptor Structure-Activity Relationship Cell Line Tumor medicine Humans Pyrroles Epidermal growth factor receptor Amines Protein Kinase Inhibitors Cell Proliferation chemistry.chemical_classification biology Chemistry Kinase Cell growth ErbB Receptors Pyrimidines src-Family Kinases Enzyme Biochemistry Cell culture biology.protein Erlotinib Proto-oncogene tyrosine-protein kinase Src medicine.drug |
| Zdroj: | European Journal of Pharmaceutical Sciences. 59:69-82 |
| ISSN: | 0928-0987 |
| DOI: | 10.1016/j.ejps.2014.04.011 |
| Popis: | The epidermal growth factor receptor is an important target in molecular cancer therapy. Herein, the enzymatic inhibition potential of a series of chiral and non chiral pyrrolopyrimidine based derivatives have been investigated and optimised. Overall, seven new compounds were identified having enzymatic IC50 values comparable to or better than the commercial drug Erlotinib. High activity was also confirmed towards the epidermal growth factor receptor L858R and L861Q mutants. Based on calculated druglike properties, eight compounds were further evaluated towards a panel of 52 other kinases revealing interesting Src-family kinase and colony stimulating factor 1 receptor kinase inhibitory activity. Cell proliferation studies with the cell lines A431, C-33A, AU-565, K-562 and genetically engineered Ba/F3-EGFR(L858R) cells also showed several molecules to be more active than Erlotinib, and thus confirming these pyrrolopyrimidines as attractive drug candidates or lead structures. |
| Databáze: | OpenAIRE |
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