| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1 Departments of Molecular and Cell Biology and Chemistry, Howard Hughes Medical Institute, The University of California; 2 Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California; 3 Division of Hematology and Oncology, Department of Medicine, Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, California; and 4 Ambit Biosciences, San Diego, California
Requests for reprints: John Kuriyan, Department of Molecular and Cell Biology, University of California at Berkeley, Barker Hall MC 3202, Berkeley, CA 94720-3202. Phone: 510-643-0137; Fax: 510-643-0159; E-mail: kuriyan{at}uclink.berkeley.edu.
We present a high-resolution (2.0 Å) crystal structure of the catalytic domain of a mutant form of the Abl tyrosine kinase (H396P; Abl-1a numbering) that is resistant to the Abl inhibitor imatinib. The structure is determined in complex with the small-molecule inhibitor VX-680 (Vertex Pharmaceuticals, Cambridge, MA), which blocks the activity of various imatinib-resistant mutant forms of Abl, including one (T315I) that is resistant to both imatinib and BMS-354825 (dasatinib), a dual Src/Abl inhibitor that seems to be clinically effective against all other imatinib-resistant forms of BCR-Abl. VX-680 is shown to have significant inhibitory activity against BCR-Abl bearing the T315I mutation in patient-derived samples. The Abl kinase domain bound to VX-680 is not phosphorylated on the activation loop in the crystal structure but is nevertheless in an active conformation, previously unobserved for Abl and inconsistent with the binding of imatinib. The adoption of an active conformation is most likely the result of synergy between the His396Pro mutation, which destabilizes the inactive conformation required for imatinib binding, and the binding of VX-680, which favors the active conformation through hydrogen bonding and steric effects. VX-680 is bound to Abl in a mode that accommodates the substitution of isoleucine for threonine at residue 315 (the "gatekeeper" position). The avoidance of the innermost cavity of the Abl kinase domain by VX-680 and the specific recognition of the active conformation explain the effectiveness of this compound against mutant forms of BCR-Abl, including those with mutations at the gatekeeper position. (Cancer Res 2006; 66(2): 1007-14)
This article has been cited by other articles:
|
|
 |
|
  X.-B. Wan, Z.-J. Long, M. Yan, J. Xu, L.-P. Xia, L. Liu, Y. Zhao, X.-F. Huang, X.-R. Wang, X.-F. Zhu, et al. Inhibition of Aurora-A suppresses epithelial-mesenchymal transition and invasion by downregulating MAPK in nasopharyngeal carcinoma cells Carcinogenesis, October 1, 2008; 29(10): 1930 - 1937. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Fiskus, Y. Wang, R. Joshi, R. Rao, Y. Yang, J. Chen, R. Kolhe, R. Balusu, K. Eaton, P. Lee, et al. Cotreatment with Vorinostat Enhances Activity of MK-0457 (VX-680) against Acute and Chronic Myelogenous Leukemia Cells Clin. Cancer Res., October 1, 2008; 14(19): 6106 - 6115. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Zhao, A. Smallwood, J. Yang, K. Koretke, K. Nurse, A. Calamari, R. B. Kirkpatrick, and Z. Lai Modulation of kinase-inhibitor interactions by auxiliary protein binding: Crystallography studies on Aurora A interactions with VX-680 and with TPX2 Protein Sci., October 1, 2008; 17(10): 1791 - 1797. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Dai, S. Chen, C. A. Venditti, X.-Y. Pei, T. K. Nguyen, P. Dent, and S. Grant Vorinostat synergistically potentiates MK-0457 lethality in chronic myelogenous leukemia cells sensitive and resistant to imatinib mesylate Blood, August 1, 2008; 112(3): 793 - 804. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Quintas-Cardama and J. Cortes Therapeutic Options Against BCR-ABL1 T315I-Positive Chronic Myelogenous Leukemia Clin. Cancer Res., July 15, 2008; 14(14): 4392 - 4399. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Vajpai, A. Strauss, G. Fendrich, S. W. Cowan-Jacob, P. W. Manley, S. Grzesiek, and W. Jahnke Solution Conformations and Dynamics of ABL Kinase-Inhibitor Complexes Determined by NMR Substantiate the Different Binding Modes of Imatinib/Nilotinib and Dasatinib J. Biol. Chem., June 27, 2008; 283(26): 18292 - 18302. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Gontarewicz, S. Balabanov, G. Keller, R. Colombo, A. Graziano, E. Pesenti, D. Benten, C. Bokemeyer, W. Fiedler, J. Moll, et al. Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I Blood, April 15, 2008; 111(8): 4355 - 4364. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. K. Kenealy, C. B. Christenson, and C. B. Williams Current Therapies for Chronic Myeloid Leukemia Journal of Pharmacy Practice, April 1, 2008; 21(2): 116 - 125. [Abstract] [PDF]
|
|
|
|
 |
|
 P. Ramirez and J. F. DiPersio Therapy Options in Imatinib Failures Oncologist, April 1, 2008; 13(4): 424 - 434. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. F. Bellon, P. Kaplan-Lefko, Y. Yang, Y. Zhang, J. Moriguchi, K. Rex, C. W. Johnson, P. E. Rose, A. M. Long, A. B. O'Connor, et al. c-Met Inhibitors with Novel Binding Mode Show Activity against Several Hereditary Papillary Renal Cell Carcinoma-related Mutations J. Biol. Chem., February 1, 2008; 283(5): 2675 - 2683. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Carpinelli, R. Ceruti, M. L. Giorgini, P. Cappella, L. Gianellini, V. Croci, A. Degrassi, G. Texido, M. Rocchetti, P. Vianello, et al. PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer Mol. Cancer Ther., December 1, 2007; 6(12): 3158 - 3168. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Guan, X.-r. Wang, X.-f. Zhu, X.-f. Huang, J. Xu, L.-h. Wang, X.-b. Wan, Z.-j. Long, J.-n. Liu, G.-k. Feng, et al. Aurora-A, a Negative Prognostic Marker, Increases Migration and Decreases Radiosensitivity in Cancer Cells Cancer Res., November 1, 2007; 67(21): 10436 - 10444. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. O'Hare, C. A. Eide, and M. W. N. Deininger Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia Blood, October 1, 2007; 110(7): 2242 - 2249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Modugno, E. Casale, C. Soncini, P. Rosettani, R. Colombo, R. Lupi, L. Rusconi, D. Fancelli, P. Carpinelli, A. D. Cameron, et al. Crystal Structure of the T315I Abl Mutant in Complex with the Aurora Kinases Inhibitor PHA-739358 Cancer Res., September 1, 2007; 67(17): 7987 - 7990. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Rahmani, T. K. Nguyen, P. Dent, and S. Grant The Multikinase Inhibitor Sorafenib Induces Apoptosis in Highly Imatinib Mesylate-Resistant Bcr/Abl+ Human Leukemia Cells in Association with Signal Transducer and Activator of Transcription 5 Inhibition and Myeloid Cell Leukemia-1 Down-Regulation Mol. Pharmacol., September 1, 2007; 72(3): 788 - 795. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. W. Wilkinson, R. Odedra, S. P. Heaton, S. R. Wedge, N. J. Keen, C. Crafter, J. R. Foster, M. C. Brady, A. Bigley, E. Brown, et al. AZD1152, a Selective Inhibitor of Aurora B Kinase, Inhibits Human Tumor Xenograft Growth by Inducing Apoptosis Clin. Cancer Res., June 15, 2007; 13(12): 3682 - 3688. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. K. Nguyen, M. Rahmani, H. Harada, P. Dent, and S. Grant MEK1/2 inhibitors sensitize Bcr/Abl+ human leukemia cells to the dual Abl/Src inhibitor BMS-354/825 Blood, May 1, 2007; 109(9): 4006 - 4015. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Soverini, I. Iacobucci, M. Baccarani, and G. Martinelli Targeted therapy and the T315I mutation in Philadelphia-positive leukemias Haematologica, April 1, 2007; 92(4): 437 - 439. [Full Text] [PDF]
|
|
|
|
|
|
S. Soverini, S. Colarossi, A. Gnani, F. Castagnetti, G. Rosti, C. Bosi, S. Paolini, M. Rondoni, P. P. Piccaluga, F. Palandri, et al. Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain Haematologica, March 1, 2007; 92(3): 401 - 404. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. M. Kantarjian, F. Giles, A. Quintas-Cardama, and J. Cortes Important Therapeutic Targets in Chronic Myelogenous Leukemia Clin. Cancer Res., February 15, 2007; 13(4): 1089 - 1097. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Martinelli, S. Soverini, I. Iacobucci, and M. Baccarani MK-0457: a light at the end of the tunnel? Blood, January 15, 2007; 109(2): 396 - 397. [Full Text] [PDF]
|
|
|
|
|
|
F. J. Giles, J. Cortes, D. Jones, D. Bergstrom, H. Kantarjian, and S. J. Freedman MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation Blood, January 15, 2007; 109(2): 500 - 502. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Puttini, A. M. L. Coluccia, F. Boschelli, L. Cleris, E. Marchesi, A. Donella-Deana, S. Ahmed, S. Redaelli, R. Piazza, V. Magistroni, et al. In vitro and In vivo Activity of SKI-606, a Novel Src-Abl Inhibitor, against Imatinib-Resistant Bcr-Abl+ Neoplastic Cells Cancer Res., December 1, 2006; 66(23): 11314 - 11322. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Lierman, C. Folens, E. H. Stover, N. Mentens, H. Van Miegroet, W. Scheers, M. Boogaerts, P. Vandenberghe, P. Marynen, and J. Cools Sorafenib is a potent inhibitor of FIP1L1-PDGFR{alpha} and the imatinib-resistant FIP1L1-PDGFR{alpha} T674I mutant Blood, August 15, 2006; 108(4): 1374 - 1376. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Mauro Defining and Managing Imatinib Resistance Hematology, January 1, 2006; 2006(1): 219 - 225. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
