Inhibitors of the Abl kinase directed at either the ATP- or myristate-binding site |
| |
Authors: | Doriano Fabbro Paul W Manley Wolfgang Jahnke Janis Liebetanz Alexandra Szyttenholm Gabriele Fendrich Andre Strauss Jianming Zhang Nathanael S Gray Francisco Adrian Markus Warmuth Xavier Pelle Robert Grotzfeld Frederic Berst Andreas Marzinzik Sandra W Cowan-Jacob Pascal Furet Jürgen Mestan |
| |
Institution: | 1. Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland;2. GNF, La Jolla, CA, USA;3. Dana Farber Cancer Insitute, Boston, MA, USA |
| |
Abstract: | 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. |
| |
Keywords: | Abl Imatinib resistance Myristate binders Kinase inhibitors Abl structure |
本文献已被 ScienceDirect 等数据库收录! |
|