Allosteric inhibitors of Bcr-abl–dependent cell proliferation
| Autor: | Jürgen Mestan, Taebo Sim, Francisco Adrian, Wooyoung Hur, Anastasia Velentza, Paul W. Manley, Guobao Zhang, Sheng Ding, Doriano Fabbro, Yi Liu, Nathanael S. Gray, Christine Sloan, Qiang Ding |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Protein Conformation
Allosteric regulation Fusion Proteins bcr-abl Antineoplastic Agents Apoptosis Biology Piperazines Cell Line Mice Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases medicine Animals Humans Kinase activity Protein Kinase Inhibitors neoplasms Molecular Biology Cell Line Transformed Cell Proliferation Kinase Imatinib Cell Biology Protein-Tyrosine Kinases medicine.disease Cell biology Pyrimidines Imatinib mesylate Drug Resistance Neoplasm Benzamides Imatinib Mesylate Signal transduction Tyrosine kinase Protein Binding medicine.drug Chronic myelogenous leukemia |
| Zdroj: | Nature Chemical Biology. 2:95-102 |
| ISSN: | 1552-4469 1552-4450 |
| Popis: | Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized at the molecular level by the expression of Bcr-abl, a 210-kDa fusion protein with deregulated tyrosine kinase activity. Encouraged by the clinical validation of Bcr-abl as the target for the treatment of CML by imatinib, we sought to identify pharmacological agents that could target this kinase by a distinct mechanism. We report the discovery of a new class of Bcr-abl inhibitors using an unbiased differential cytotoxicity screen of a combinatorial kinase-directed heterocycle library. Compounds in this class (exemplified by GNF-2) show exclusive antiproliferative activity toward Bcr-abl-transformed cells, with potencies similar to imatinib, while showing no inhibition of the kinase activity of full-length or catalytic domain of c-abl. We propose that this new class of compounds inhibits Bcr-abl kinase activity through an allosteric non-ATP competitive mechanism. |
| Databáze: | OpenAIRE |
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