Second Generation Abl Tyrosine Kinase Inhibitors and Novel Compounds to Eliminate the Bcr-Abl/T315I Clone (Second Edition)

The first line therapy for chronic myeloid leukemia (CML) was dramatically altered within a few years of the introduction of Abl specific tyrosine kinase inhibitor, imatinib mesylate to the clinic. However, refractoriness and early relapse have frequently been reported, particularly in patients with advanced-stage disease. Point mutations within the Abl kinase domain that interfere with imatinib mesylate binding are most critical cause of imatinib resistance. To override resistance, four second generation ATP competitive Abl kinase inhibitors such as dasatinib, nilotinib, bosutnib and bafetinib have been developed. Although these inhibitors can inhibit the phosphorylation of most mutated Bcr-Abl, none of these are effective for T315I. Thus, Bcr-Abl/T315I is an important and challenging target for discovery of CML therapeutics. Novel agents such as ATP noncompetitive Abl kinase inhibitors and multikinase inhibitors including Aurora kinase which can inhibit the phosphorylation of Bcr-Abl/T315I have been developed. This review is focused on the novel compounds which claim the efficacy against Bcr-Abl/T315I.

Keywords: Bcr-Abl, imatinib mesylate, SGX, cyclin dependent kinase, hydrazine derivatives