Structure guided optimization of a fragment hit to imidazopyridine inhibitors of PI3K
| Autor: | Aaron Smith, Matthew Burger, Charles Voliva, Kay Huh, John Chan, Sabina Pecchi, Johanna Janssen, Jiong Lan, Hanne Merritt, Marion Wiesmann, Wooseok Han, Zhi-Jie Ni, Susan Kaufman, Mark Knapp |
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| Rok vydání: | 2013 |
| Předmět: |
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Molecular Imidazopyridine Pyridines Clinical Biochemistry Cell Pharmaceutical Science Imides Biochemistry chemistry.chemical_compound Inhibitory Concentration 50 Structure-Activity Relationship Cell Line Tumor Drug Discovery Gene duplication medicine Humans Benzothiazoles Enzyme Inhibitors Molecular Biology PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors Chemistry Kinase Organic Chemistry Cancer medicine.disease In vitro Enzyme Activation medicine.anatomical_structure Benzothiazole Solubility Cancer research Molecular Medicine Female Azo Compounds |
| Zdroj: | Bioorganicmedicinal chemistry letters. 23(16) |
| ISSN: | 1464-3405 |
| Popis: | PI3 kinases are a family of lipid kinases mediating numerous cell processes such as proliferation, migration and differentiation. The PI3 Kinase pathway is often de-regulated in cancer through PI3Kα overexpression, gene amplification, mutations and PTEN phosphatase deletion. PI3K inhibitors represent therefore an attractive therapeutic modality for cancer treatment. Herein we describe how the potency of a benzothiazole fragment hit was quickly improved based on structural information and how this early chemotype was further optimized through scaffold hopping. This effort led to the identification of a series of 2-acetamido-5-heteroaryl imidazopyridines showing potent in vitro activity against all class I PI3Ks and attractive pharmacokinetic properties. |
| Databáze: | OpenAIRE |
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