Inhibitors of the Abl kinase directed at either the ATP- or myristate-binding site
| Autor: | Francisco Adrian, Janis Liebetanz, André Strauss, Sandra W. Cowan-Jacob, Andreas Marzinzik, Xavier Pelle, Pascal Furet, Frederic Berst, Jürgen Mestan, Paul W. Manley, Gabriele Fendrich, Robert Martin Grotzfeld, Nathanael S. Gray, Markus Warmuth, Doriano Fabbro, Jianming Zhang, Alexandra Szyttenholm, Wolfgang Jahnke |
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| Rok vydání: | 2010 |
| Předmět: |
Allosteric regulation
Mutation Missense Biophysics Biology Crystallography X-Ray Myristic Acid Biochemistry Piperazines Analytical Chemistry Adenosine Triphosphate Allosteric Regulation Neoplasms hemic and lymphatic diseases medicine Humans Proto-Oncogene Proteins c-abl Nuclear Magnetic Resonance Biomolecular Protein Kinase Inhibitors neoplasms Molecular Biology ABL Kinase Protein Structure Tertiary Dasatinib Pyrimidines Imatinib mesylate Nilotinib Protein kinase domain Drug Resistance Neoplasm Benzamides Imatinib Mesylate Proto-oncogene tyrosine-protein kinase Src medicine.drug |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1804:454-462 |
| ISSN: | 1570-9639 |
| DOI: | 10.1016/j.bbapap.2009.12.009 |
| Popis: | The ATP-competitive inhibitors dasatinib and nilotinib, which bind to catalytically different conformations of the Abl kinase domain, have recently been approved for the treatment of imatinib-resistant CML. These two new drugs, albeit very efficient against most of the imatinib-resistant mutants of Bcr-Abl, fail to effectively suppress the Bcr-Abl activity of the T315I (or gatekeeper) mutation. Generating new ATP site-binding drugs that target the T315I in Abl has been hampered, amongst others, by target selectivity, which is frequently an issue when developing ATP-competitive inhibitors. Recently, using an unbiased cellular screening approach, GNF-2, a non-ATP-competitive inhibitor, has been identified that demonstrates cellular activity against Bcr-Abl transformed cells. The exquisite selectivity of GNF-2 is due to the finding that it targets the myristate binding site located near the C-terminus of the Abl kinase domain, as demonstrated by genetic approaches, solution NMR and X-ray crystallography. GNF-2, like myristate, is able to induce and/or stabilize the clamped inactive conformation of Abl analogous to the SH2-Y527 interaction of Src. The molecular mechanism for allosteric inhibition by the GNF-2 inhibitor class, and the combined effects with ATP-competitive inhibitors such as nilotinib and imatinib on wild-type Abl and imatinib-resistant mutants, in particular the T315I gatekeeper mutant, are reviewed. |
| Databáze: | OpenAIRE |
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