Inhibitors of the Abl kinase directed at either the ATP- or myristate-binding site.

Research paper by Doriano D Fabbro, Paul W PW Manley, Wolfgang W Jahnke, Janis J Liebetanz, Alexandra A Szyttenholm, Gabriele G Fendrich, Andre A Strauss, Jianming J Zhang, Nathanael S NS Gray, Francisco F Adrian, Markus M Warmuth, Xavier X Pelle, Robert R Grotzfeld, Frederic F Berst, Andreas A Marzinzik, et al.

Indexed on: 16 Feb '10Published on: 16 Feb '10Published in: Biochimica et biophysica acta


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.