Bcr-Abl, a fusion protein with deregulated tyrosine kinase activity, is highly expressed in chronic myelogenous leukemia. GNF-5 is the N-hydroxyethyl carboamide analog of GNF-2 , a selective allosteric inhibitor of Bcr-Abl. GNF-5 demonstrates IC50 values of 4.52, 0.38, and 0.93 μM against Bcr-Abl mutants G250E, E255V, and M351T, respectively. When used in combination with the ATP-competitive Bcr-Abl inhibitors imatinib or nilotinib , GNF-5 displays additive inhibitory activity against T315I Bcr-Abl mutants both in in vitro assays and in a recalcitrant T315I Bcr-Abl mutant mouse bone marrow transplantation model.
