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The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABL Mutants
Open accessAbstract
Chronic myeloid leukemia (CML) is caused by the constitutively activated tyrosine kinase breakpoint cluster (BCR)-ABL. Current frontline therapy for CML is imatinib, an inhibitor of BCR-ABL. Although imatinib has a high rate of clinical success in early phase CML, treatment resistance is problematic, particularly in later stages of the disease, and is frequently mediated by mutations in BCR-ABL. Dasatinib (BMS-354825) is a multitargeted tyrosine kinase inhibitor that targets oncogenic pathways and is a more potent inhibitor than imatinib against wild-type BCR-ABL. It has also shown preclinical activity against all but one of the imatinib-resistant BCR-ABL mutants tested to date. Analysis of the crystal structure of dasatinib-bound ABL kinase suggests that the increased binding affinity of dasatinib over imatinib is at least partially due to its ability to recognize multiple states of BCR-ABL. The structure also provides an explanation for the activity of dasatinib against imatinib-resistant BCR-ABL mutants. (Cancer Res 2006; 66(11): 5790-7)
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[20] Processing of X-ray diffraction data collected in oscillation mode
Otwinowski, Z., & Minor, W. (1997) · Methods in Enzymology · doi:10.1016/s0076-6879(97)76066-x · Cited by 33,475
Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification
Gorre, M. E., Mohammed, M., Ellwood, K., Hsu, N., Paquette, R., Rao, P. N., & Sawyers, C. L. (2001) · Science · doi:10.1126/science.1062538 · Cited by 3,104
O'Hare, T., Walters, D. K., Stoffregen, E. P., Jia, T., Manley, P. W., Mestan, J., Cowan-Jacob, S. W., Lee, F. Y., Heinrich, M. C., Deininger, M. W. N., et al. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-0259 · Cited by 1,036
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Cited by
O'Hare, T., Shakespeare, W. C., Zhu, X., Eide, C. A., Rivera, V. M., Wang, F., Adrian, L. T., Zhou, T., Huang, W.-S., Xu, Q., et al. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.09.028 · Cited by 1,259
Roskoski, R. (2016) · Pharmacological Research · doi:10.1016/j.phrs.2015.10.021 · Cited by 886
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Quintás-Cardama, A., & Cortes, J. (2009) · Blood · doi:10.1182/blood-2008-03-144790 · Cited by 745
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Druker, B. J. (2008) · Blood · doi:10.1182/blood-2008-07-077958 · Cited by 668
Metadata
- Authors
- Tokarski, J. S., Newitt, J. A., Chang, C. Y. J., Cheng, J. D., Wittekind, M., Kiefer, S. E., Kish, K., Lee, F. Y. F., Borzillerri, R., Lombardo, L. J., Xie, D., Zhang, Y., & Klei, H. E.
- Venue
- Cancer Research
- Published
- 2006-06-01
- Volume
- 66
- Issue
- 11
- Pages
- 5790-5797
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2101635775
- Cited by
- 700
- References
- 3
- FWCI
- 32.06
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Tokarski, J. S., Newitt, J. A., Chang, C. Y. J., Cheng, J. D., Wittekind, M., Kiefer, S. E., Kish, K., Lee, F. Y. F., Borzillerri, R., Lombardo, L. J., Xie, D., Zhang, Y., & Klei, H. E. (2006). The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABL Mutants. Cancer Research. https://doi.org/10.1158/0008-5472.can-05-4187
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
