Exploring the Chemical Space around the Privileged Pyrazolo[3,4-d]pyrimidine Scaffold: Toward Novel Allosteric Inhibitors of T315I-Mutated Abl
| Autor: | Martina Mencarelli, Miroslava Kissova, Silvia Schenone, Giovanni Maga, Maurizio Botta, Marco Radi, Giulia Vignaroli, Deborah Sementa, Emmanuele Crespan |
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| Rok vydání: | 2014 |
| Předmět: |
pyrazolo-pyrimidines
Pyrimidine Stereochemistry Allosteric regulation Fusion Proteins bcr-abl Allosteric inhibitors T315I mutation Structure-Activity Relationship chemistry.chemical_compound Non-competitive inhibition Allosteric Regulation hemic and lymphatic diseases Protein Kinase Inhibitors chemistry.chemical_classification ABL Dose-Response Relationship Drug Molecular Structure Chemistry Kinase General Chemistry General Medicine Chemical space Pyrimidines Enzyme Biochemistry Pyrazoles Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | ACS Combinatorial Science. 16:168-175 |
| ISSN: | 2156-8944 2156-8952 |
| Popis: | A library of pyrazolo[3,4-d]pyrimidines, endowed with a high level of molecular diversity, has been developed applying a synthetic sequence that allowed C3, N1, C4, and C6 substitution. The enzymatic screening of this "privileged scaffold"-based compound collection, validated the use of a diversity-oriented approach in a field characteristically explored by target-oriented synthesis. In fact, several compounds showed high activity against the selected kinases (i.e., Src, Abl wt, and T315I mutated-form), furthermore and interestingly a new compound has emerged as an allosteric inhibitor of the T315I mutated-form of Abl, opening up new opportunities for the development of a novel class of noncompetitive inhibitors of Abl (T315I). |
| Databáze: | OpenAIRE |
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