The Ins and Outs of Bcr-Abl Inhibition
- 1 May 2012
- journal article
- Published by SAGE Publications in Genes & Cancer
- Vol. 3 (5-6), 447-454
- https://doi.org/10.1177/1947601912462126
Abstract
The development of inhibitors against Abl has changed the landscape for the treatment of chronic myelogenous leukemia (CML) and cancer in general. Beginning with the monumental discovery and approval of imatinib for CML, a second generation of inhibitors, nilotinib and dasatinib, has now gained approval for the treatment of CML. Notably, these second-generation inhibitors are active against many of the mutations in the Abl kinase that confer resistance to imatinib. However, resistance remains a major problem, and new inhibitors such as ponatinib and GNF2/GNF5 have been developed, with activity towards the common gatekeeper T315I mutation. We review here the mechanisms of Abl inhibition with an emphasis on structural elements that are important for the selectivity and design of new molecules. In particular, we focus on how changes in the conformation of the P-loop, the activation loop, the DFG motif, and other structural elements of Abl have been instrumental in developing an understanding of inhibitor binding.Keywords
This publication has 39 references indexed in Scilit:
- Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid LeukemiaThe New England Journal of Medicine, 2006
- Surface comparison of active and inactive protein kinases identifies a conserved activation mechanismProceedings of the National Academy of Sciences of the United States of America, 2006
- Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylateLeukemia, 2006
- Dasatinib in Imatinib-Resistant Philadelphia Chromosome–Positive LeukemiasThe New England Journal of Medicine, 2006
- Nilotinib in Imatinib-Resistant CML and Philadelphia Chromosome–Positive ALLThe New England Journal of Medicine, 2006
- The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABL MutantsCancer Research, 2006
- A Src-Like Inactive Conformation in the Abl Tyrosine Kinase DomainPLoS Biology, 2006
- Characterization of AMN107, a selective inhibitor of native and mutant Bcr-AblCancer Cell, 2005
- Overriding Imatinib Resistance with a Novel ABL Kinase InhibitorScience, 2004
- Imatinib (STI571) Resistance in Chronic Myelogenous Leukemia: Molecular Basis of the Underlying Mechanisms and Potential Strategies for TreatmentMini-Reviews in Medicinal Chemistry, 2004