Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 289 (5486): 1938-1942

Copyright © 2000 by the American Association for the Advancement of Science

Structural Mechanism for STI-571 Inhibition of Abelson Tyrosine Kinase

Thomas Schindler,1 William Bornmann,3 Patricia Pellicena,4 W. Todd Miller,4 Bayard Clarkson,3 John Kuriyan12*

The inadvertent activation of the Abelson tyrosine kinase (Abl) causes chronic myelogenous leukemia (CML). A small-molecule inhibitor of Abl (STI-571) is effective in the treatment of CML. We report the crystal structure of the catalytic domain of Abl, complexed to a variant of STI-571. Critical to the binding of STI-571 is the adoption by the kinase of an inactive conformation, in which a centrally located "activation loop" is not phosphorylated. The conformation of this loop is distinct from that in active protein kinases, as well as in the inactive form of the closely related Src kinases. These results suggest that compounds that exploit the distinctive inactivation mechanisms of individual protein kinases can achieve both high affinity and high specificity.

1 Laboratories of Molecular Biophysics and
2 Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
3 Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
4 Department of Physiology and Biophysics, School of Medicine, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.
*   To whom correspondence should be addressed. E-mail: kuriyan{at}rockefeller.edu



THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Clinical Targeting of Mutated and Wild-Type Protein Tyrosine Kinases in Cancer.
J. M. Drake, J. K. Lee, and O. N. Witte (2014)
Mol. Cell. Biol. 34, 1722-1732
   Abstract »    Full Text »    PDF »
New Chemical Scaffolds for Human African Trypanosomiasis Lead Discovery from a Screen of Tyrosine Kinase Inhibitor Drugs.
R. Behera, S. M. Thomas, and K. Mensa-Wilmot (2014)
Antimicrob. Agents Chemother. 58, 2202-2210
   Abstract »    Full Text »    PDF »
Molecular dynamics reveal BCR-ABL1 polymutants as a unique mechanism of resistance to PAN-BCR-ABL1 kinase inhibitor therapy.
D. L. Gibbons, S. Pricl, P. Posocco, E. Laurini, M. Fermeglia, H. Sun, M. Talpaz, N. Donato, and A. Quintas-Cardama (2014)
PNAS 111, 3550-3555
   Abstract »    Full Text »    PDF »
NMR reveals the allosteric opening and closing of Abelson tyrosine kinase by ATP-site and myristoyl pocket inhibitors.
L. Skora, J. Mestan, D. Fabbro, W. Jahnke, and S. Grzesiek (2013)
PNAS 110, E4437-E4445
   Abstract »    Full Text »    PDF »
Inhibition of spleen tyrosine kinase in the treatment of rheumatoid arthritis.
J. S. Nijjar, A. Tindell, I. B. McInnes, and S. Siebert (2013)
Rheumatology 52, 1556-1562
   Abstract »    Full Text »    PDF »
A Kinetic Test Characterizes Kinase Intramolecular and Intermolecular Autophosphorylation Mechanisms.
C. A. Dodson, S. Yeoh, T. Haq, and R. Bayliss (2013)
Science Signaling 6, ra54
   Abstract »    Full Text »    PDF »
Threshold Levels of ABL Tyrosine Kinase Inhibitors Retained in Chronic Myeloid Leukemia Cells Determine Their Commitment to Apoptosis.
T. O'Hare, C. A. Eide, A. Agarwal, L. T. Adrian, M. S. Zabriskie, R. J. MacKenzie, D. H. LaTocha, K. J. Johnson, H. You, J. Luo, et al. (2013)
Cancer Res. 73, 3356-3370
   Abstract »    Full Text »    PDF »
An analogue-sensitive approach identifies basal body rotation and flagellum attachment zone elongation as key functions of PLK in Trypanosoma brucei.
A. Lozano-Nunez, K. N. Ikeda, T. Sauer, and C. L. de Graffenried (2013)
Mol. Biol. Cell 24, 1321-1333
   Abstract »    Full Text »    PDF »
Enhanced SH3/Linker Interaction Overcomes Abl Kinase Activation by Gatekeeper and Myristic Acid Binding Pocket Mutations and Increases Sensitivity to Small Molecule Inhibitors.
S. Panjarian, R. E. Iacob, S. Chen, T. E. Wales, J. R. Engen, and T. E. Smithgall (2013)
J. Biol. Chem. 288, 6116-6129
   Abstract »    Full Text »    PDF »
Emerging Roles of SIRT1 in Cancer Drug Resistance.
Z. Wang and W. Chen (2013)
Genes & Cancer 4, 82-90
   Abstract »    Full Text »    PDF »
Structure and Dynamic Regulation of Abl Kinases.
S. Panjarian, R. E. Iacob, S. Chen, J. R. Engen, and T. E. Smithgall (2013)
J. Biol. Chem. 288, 5443-5450
   Abstract »    Full Text »    PDF »
Explaining why Gleevec is a specific and potent inhibitor of Abl kinase.
Y.-L. Lin, Y. Meng, W. Jiang, and B. Roux (2013)
PNAS 110, 1664-1669
   Abstract »    Full Text »    PDF »
On the molecular mechanisms of mitotic kinase activation.
R. Bayliss, A. Fry, T. Haq, and S. Yeoh (2012)
Open Bio 2, 120136
   Abstract »    Full Text »    PDF »
Identifying mechanism-of-action targets for drugs and probes.
E. Gregori-Puigjane, V. Setola, J. Hert, B. A. Crews, J. J. Irwin, E. Lounkine, L. Marnett, B. L. Roth, and B. K. Shoichet (2012)
PNAS 109, 11178-11183
   Abstract »    Full Text »    PDF »
Bioinformatics and variability in drug response: a protein structural perspective.
J. L. Lahti, G. W. Tang, E. Capriotti, T. Liu, and R. B. Altman (2012)
J R Soc Interface 9, 1409-1437
   Abstract »    Full Text »    PDF »
Structure, Regulation, Signaling, and Targeting of Abl Kinases in Cancer.
O. Hantschel (2012)
Genes & Cancer 3, 436-446
   Abstract »    Full Text »    PDF »
The Ins and Outs of Bcr-Abl Inhibition.
E. P. Reddy and A. K. Aggarwal (2012)
Genes & Cancer 3, 447-454
   Abstract »    Full Text »    PDF »
Modelling dynamics in protein crystal structures by ensemble refinement.
B. T. Burnley, P. V. Afonine, P. D. Adams, and P. Gros (2012)
eLife Sci 1, e00311
   Abstract »    Full Text »    PDF »
Characterization of kinase inhibitors using different phosphorylation states of colony stimulating factor-1 receptor tyrosine kinase.
D. Kitagawa, M. Gouda, Y. Kirii, N. Sugiyama, Y. Ishihama, I. Fujii, Y. Narumi, K. Akita, and K. Yokota (2012)
J. Biochem. 151, 47-55
   Abstract »    Full Text »    PDF »
The BCR-ABL35INS insertion/truncation mutant is kinase-inactive and does not contribute to tyrosine kinase inhibitor resistance in chronic myeloid leukemia.
T. O'Hare, M. S. Zabriskie, C. A. Eide, A. Agarwal, L. T. Adrian, H. You, A. S. Corbin, F. Yang, R. D. Press, V. M. Rivera, et al. (2011)
Blood 118, 5250-5254
   Abstract »    Full Text »    PDF »
Molecular Mechanism of Selectivity among G Protein-Coupled Receptor Kinase 2 Inhibitors.
D. M. Thal, R. Y. Yeow, C. Schoenau, J. Huber, and J. J. G. Tesmer (2011)
Mol. Pharmacol. 80, 294-303
   Abstract »    Full Text »    PDF »
c-MYC Oncoprotein Dictates Transcriptional Profiles of ATP-Binding Cassette Transporter Genes in Chronic Myelogenous Leukemia CD34+ Hematopoietic Progenitor Cells.
A. Porro, N. Iraci, S. Soverini, D. Diolaiti, S. Gherardi, C. Terragna, S. Durante, E. Valli, T. Kalebic, R. Bernardoni, et al. (2011)
Mol. Cancer Res. 9, 1054-1066
   Abstract »    Full Text »    PDF »
Targeting mutations predictably.
H. Schreiber, J. D. Rowley, and D. A. Rowley (2011)
Blood 118, 830-831
   Full Text »    PDF »
The Host Phosphoinositide 5-Phosphatase SHIP2 Regulates Dissemination of Vaccinia Virus.
S. McNulty, K. Powell, C. Erneux, and D. Kalman (2011)
J. Virol. 85, 7402-7410
   Abstract »    Full Text »    PDF »
Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation.
J. A. Janas and L. Van Aelst (2011)
Mol. Cell. Biol. 31, 2552-2565
   Abstract »    Full Text »    PDF »
Profile of Charles L. Sawyers.
P. Nair (2011)
PNAS 108, 10033-10035
   Full Text »    PDF »
Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A.
A. Salas, S. Ponnusamy, C. E. Senkal, M. Meyers-Needham, S. P. Selvam, S. A. Saddoughi, E. Apohan, R. D. Sentelle, C. Smith, C. R. Gault, et al. (2011)
Blood 117, 5941-5952
   Abstract »    Full Text »    PDF »
Altered Expression of Circadian Clock Genes in Human Chronic Myeloid Leukemia.
M.-Y. Yang, W.-C. Yang, P.-M. Lin, J.-F. Hsu, H.-H. Hsiao, Y.-C. Liu, H.-J. Tsai, C.-S. Chang, and S.-F. Lin (2011)
J Biol Rhythms 26, 136-148
   Abstract »    PDF »
Genetic and Pharmacological Inhibition of PDK1 in Cancer Cells: CHARACTERIZATION OF A SELECTIVE ALLOSTERIC KINASE INHIBITOR.
K. Nagashima, S. D. Shumway, S. Sathyanarayanan, A. H. Chen, B. Dolinski, Y. Xu, H. Keilhack, T. Nguyen, M. Wiznerowicz, L. Li, et al. (2011)
J. Biol. Chem. 286, 6433-6448
   Abstract »    Full Text »    PDF »
C-KIT mutation cooperates with full-length AML1-ETO to induce acute myeloid leukemia in mice.
Y.-Y. Wang, L.-J. Zhao, C.-F. Wu, P. Liu, L. Shi, Y. Liang, S.-M. Xiong, J.-Q. Mi, Z. Chen, R. Ren, et al. (2011)
PNAS 108, 2450-2455
   Abstract »    Full Text »    PDF »
OCT-1 function varies with cell lineage but is not influenced by BCR-ABL.
J. R. Engler, A. C. W. Zannettino, C. G. Bailey, J. E. J. Rasko, T. P. Hughes, and D. L. White (2011)
Haematologica 96, 213-220
   Abstract »    Full Text »    PDF »
Targeting the BCR-ABL Signaling Pathway in Therapy-Resistant Philadelphia Chromosome-Positive Leukemia.
T. O'Hare, M. W. N. Deininger, C. A. Eide, T. Clackson, and B. J. Druker (2011)
Clin. Cancer Res. 17, 212-221
   Abstract »    Full Text »    PDF »
A Fluorescence Lifetime-Based Assay for Abelson Kinase.
S. Pritz, G. Meder, K. Doering, P. Drueckes, J. Woelcke, L. M. Mayr, and U. Hassiepen (2011)
J Biomol Screen 16, 65-72
   Abstract »    Full Text »    PDF »
From Hen House to Bedside: Tracing Hanafusa's Legacy from Avian Leukemia Viruses to SRC to ABL and Beyond.
M. G. Kharas and G. Q. Daley (2010)
Genes & Cancer 1, 1164-1169
   Abstract »    Full Text »    PDF »
Kinase-mediated quasi-dimers of EGFR.
E. M. Bublil, G. Pines, G. Patel, G. Fruhwirth, T. Ng, and Y. Yarden (2010)
FASEB J 24, 4744-4755
   Abstract »    Full Text »    PDF »
Bag1 directly routes immature BCR-ABL for proteasomal degradation.
F. Tsukahara and Y. Maru (2010)
Blood 116, 3582-3592
   Abstract »    Full Text »    PDF »
Exon 7 Deletion in the bcr-abl Gene Is Frequent in Chronic Myeloid Leukemia Patients and Is Not Correlated with Resistance against Imatinib.
J.-B. Gaillard, C. Arnould, S. Bravo, D. Donadio, C. Exbrayat, E. Jourdan, D. Reboul, J. Chiesa, and T. Lavabre-Bertrand (2010)
Mol. Cancer Ther. 9, 3083-3089
   Abstract »    Full Text »    PDF »
Real-time Fluorescent Resonance Energy Transfer Analysis to Monitor Drug Resistance in Chronic Myelogenous Leukemia.
A. Tunceroglu, M. Matsuda, and R. B. Birge (2010)
Mol. Cancer Ther. 9, 3065-3073
   Abstract »    Full Text »    PDF »
BCR-ABL SH3-SH2 domain mutations in chronic myeloid leukemia patients on imatinib.
D. W. Sherbenou, O. Hantschel, I. Kaupe, S. Willis, T. Bumm, L. P. Turaga, T. Lange, K.-H. Dao, R. D. Press, B. J. Druker, et al. (2010)
Blood 116, 3278-3285
   Abstract »    Full Text »    PDF »
Activity of the multitargeted kinase inhibitor, AT9283, in imatinib-resistant BCR-ABL-positive leukemic cells.
R. Tanaka, M. S. Squires, S. Kimura, A. Yokota, R. Nagao, T. Yamauchi, M. Takeuchi, H. Yao, M. Reule, T. Smyth, et al. (2010)
Blood 116, 2089-2095
   Abstract »    Full Text »    PDF »
Crystal Structure of Staphylococcus aureus Metallopeptidase (Sapep) Reveals Large Domain Motions between the Manganese-bound and Apo-states.
T. S. Girish and B. Gopal (2010)
J. Biol. Chem. 285, 29406-29415
   Abstract »    Full Text »    PDF »
ABL Tyrosine Kinases: Evolution of Function, Regulation, and Specificity.
J. Colicelli (2010)
Science Signaling 3, re6
   Abstract »    Full Text »    PDF »
Classic and contemporary approaches to modeling biochemical reactions.
W. W. Chen, M. Niepel, and P. K. Sorger (2010)
Genes & Dev. 24, 1861-1875
   Abstract »    Full Text »    PDF »
Expression of a Src Family Kinase in Chronic Myelogenous Leukemia Cells Induces Resistance to Imatinib in a Kinase-dependent Manner.
T. Pene-Dumitrescu and T. E. Smithgall (2010)
J. Biol. Chem. 285, 21446-21457
   Abstract »    Full Text »    PDF »
Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFR{alpha}, Kit, and Src kinases: novel type II inhibitor of gatekeeper mutants.
E. Weisberg, H. G. Choi, A. Ray, R. Barrett, J. Zhang, T. Sim, W. Zhou, M. Seeliger, M. Cameron, M. Azam, et al. (2010)
Blood 115, 4206-4216
   Abstract »    Full Text »    PDF »
Abl Family Tyrosine Kinases Regulate Sialylated Ganglioside Receptors for Polyomavirus.
A. I. Swimm, W. Bornmann, M. Jiang, M. J. Imperiale, A. E. Lukacher, and D. Kalman (2010)
J. Virol. 84, 4243-4251
   Abstract »    Full Text »    PDF »
Molecular Dynamics Simulations Show That Conformational Selection Governs the Binding Preferences of Imatinib for Several Tyrosine Kinases.
A. Aleksandrov and T. Simonson (2010)
J. Biol. Chem. 285, 13807-13815
   Abstract »    Full Text »    PDF »
Critical Role of the Platelet-derived Growth Factor Receptor (PDGFR) {beta} Transmembrane Domain in the TEL-PDGFR{beta} Cytosolic Oncoprotein.
F. Toffalini, C. Hellberg, and J. B. Demoulin (2010)
J. Biol. Chem. 285, 12268-12278
   Abstract »    Full Text »    PDF »
Disruption of angiogenesis and tumor growth with an orally active drug that stabilizes the inactive state of PDGFR{beta}/B-RAF.
E. A. Murphy, D. J. Shields, K. Stoletov, E. Dneprovskaia, M. McElroy, J. I. Greenberg, J. Lindquist, L. M. Acevedo, S. Anand, B. K. Majeti, et al. (2010)
PNAS 107, 4299-4304
   Abstract »    Full Text »    PDF »
Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter?.
S. Branford, J. V. Melo, and T. P. Hughes (2009)
Blood 114, 5426-5435
   Abstract »    Full Text »    PDF »
Mechanisms of Resistance to Imatinib and Second-Generation Tyrosine Inhibitors in Chronic Myeloid Leukemia.
D. Milojkovic and J. Apperley (2009)
Clin. Cancer Res. 15, 7519-7527
   Abstract »    Full Text »    PDF »
Acute dasatinib exposure commits Bcr-Abl-dependent cells to apoptosis.
J. L. Snead, T. O'Hare, L. T. Adrian, C. A. Eide, T. Lange, B. J. Druker, and M. W. Deininger (2009)
Blood 114, 3459-3463
   Abstract »    Full Text »    PDF »
Regulation of cell migration and morphogenesis by Abl-family kinases: emerging mechanisms and physiological contexts.
W. D. Bradley and A. J. Koleske (2009)
J. Cell Sci. 122, 3441-3454
   Abstract »    Full Text »    PDF »
Development and Applications of a Broad-Coverage, TR-FRET-Based Kinase Binding Assay Platform.
C. S. Lebakken, S. M. Riddle, U. Singh, W. J. Frazee, H. C. Eliason, Y. Gao, L. J. Reichling, B. D. Marks, and K. W. Vogel (2009)
J Biomol Screen 14, 924-935
   Abstract »    PDF »
Substrate Recognition of Anthrax Lethal Factor Examined by Combinatorial and Pre-steady-state Kinetic Approaches.
M. Yu. Zakharova, N. A. Kuznetsov, S. A. Dubiley, A. V. Kozyr, O. S. Fedorova, D. M. Chudakov, D. G. Knorre, I. G. Shemyakin, A. G. Gabibov, and A. V. Kolesnikov (2009)
J. Biol. Chem. 284, 17902-17913
   Abstract »    Full Text »    PDF »
Discovery and Exploitation of Inhibitor-resistant Aurora and Polo Kinase Mutants for the Analysis of Mitotic Networks.
P. J. Scutt, M. L. H. Chu, D. A. Sloane, M. Cherry, C. R. Bignell, D. H. Williams, and P. A. Eyers (2009)
J. Biol. Chem. 284, 15880-15893
   Abstract »    Full Text »    PDF »
Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study.
L. Noens, M.-A. van Lierde, R. De Bock, G. Verhoef, P. Zachee, Z. Berneman, P. Martiat, P. Mineur, K. Van Eygen, K. MacDonald, et al. (2009)
Blood 113, 5401-5411
   Abstract »    Full Text »    PDF »
Structural Characterization of Proline-rich Tyrosine Kinase 2 (PYK2) Reveals a Unique (DFG-out) Conformation and Enables Inhibitor Design.
S. Han, A. Mistry, J. S. Chang, D. Cunningham, M. Griffor, P. C. Bonnette, H. Wang, B. A. Chrunyk, G. E. Aspnes, D. P. Walker, et al. (2009)
J. Biol. Chem. 284, 13193-13201
   Abstract »    Full Text »    PDF »
Structure-Activity Relationships and X-ray Structures Describing the Selectivity of Aminopyrazole Inhibitors for c-Jun N-terminal Kinase 3 (JNK3) over p38.
T. Kamenecka, J. Habel, D. Duckett, W. Chen, Y. Y. Ling, B. Frackowiak, R. Jiang, Y. Shin, X. Song, and P. LoGrasso (2009)
J. Biol. Chem. 284, 12853-12861
   Abstract »    Full Text »    PDF »
Equally Potent Inhibition of c-Src and Abl by Compounds that Recognize Inactive Kinase Conformations.
M. A. Seeliger, P. Ranjitkar, C. Kasap, Y. Shan, D. E. Shaw, N. P. Shah, J. Kuriyan, and D. J. Maly (2009)
Cancer Res. 69, 2384-2392
   Abstract »    Full Text »    PDF »
Mapping the conformational transition in Src activation by cumulating the information from multiple molecular dynamics trajectories.
S. Yang, N. K. Banavali, and B. Roux (2009)
PNAS 106, 3776-3781
   Abstract »    Full Text »    PDF »
Dasatinib dosing strategies in Philadelphia chromosome-positive leukemia.
S.-F. Wong (2009)
Journal of Oncology Pharmacy Practice 15, 17-27
   Abstract »    PDF »
Molecular biology of bcr-abl1-positive chronic myeloid leukemia.
A. Quintas-Cardama and J. Cortes (2009)
Blood 113, 1619-1630
   Abstract »    Full Text »    PDF »
Targeted Cancer Therapeutics.
W. N. Hait and T. W. Hambley (2009)
Cancer Res. 69, 1263-1267
   Abstract »    Full Text »    PDF »
KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients.
K. S. Gajiwala, J. C. Wu, J. Christensen, G. D. Deshmukh, W. Diehl, J. P. DiNitto, J. M. English, M. J. Greig, Y.-A. He, S. L. Jacques, et al. (2009)
PNAS 106, 1542-1547
   Abstract »    Full Text »    PDF »
Activity of Bosutinib, Dasatinib, and Nilotinib Against 18 Imatinib-Resistant BCR/ABL Mutants.
S. Redaelli, R. Piazza, R. Rostagno, V. Magistroni, P. Perini, M. Marega, C. Gambacorti-Passerini, and F. Boschelli (2009)
J. Clin. Oncol. 27, 469-471
   Full Text »    PDF »
A conserved protonation-dependent switch controls drug binding in the Abl kinase.
Y. Shan, M. A. Seeliger, M. P. Eastwood, F. Frank, H. Xu, M. O Jensen, R. O. Dror, J. Kuriyan, and D. E. Shaw (2009)
PNAS 106, 139-144
   Abstract »    Full Text »    PDF »
Crystal Structures of the Lyn Protein Tyrosine Kinase Domain in Its Apo- and Inhibitor-bound State.
N. K. Williams, I. S. Lucet, S. P. Klinken, E. Ingley, and J. Rossjohn (2009)
J. Biol. Chem. 284, 284-291
   Abstract »    Full Text »    PDF »
Imatinib Mesylate (STI571)-Induced Cell Edge Translocation of Kinase-Active and Kinase-Defective Abelson Kinase: Requirements of Myristoylation and src Homology 3 Domain.
A. Fujita, T. Shishido, Y. Yuan, E. Inamoto, S. Narumiya, and N. Watanabe (2009)
Mol. Pharmacol. 75, 75-84
   Abstract »    Full Text »    PDF »
Mechanisms of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia and recent therapeutic strategies to overcome resistance.
D. Bixby and M. Talpaz (2009)
Hematology 2009, 461-476
   Abstract »    Full Text »    PDF »
Toward a Cure For Chronic Myeloid Leukemia.
T. O'Hare and M. W. Deininger (2008)
Clin. Cancer Res. 14, 7971-7974
   Full Text »    PDF »
Translation of the Philadelphia chromosome into therapy for CML.
B. J. Druker (2008)
Blood 112, 4808-4817
   Abstract »    Full Text »    PDF »
Tyrosine Phosphorylation of the Nuclear Receptor Coactivator AIB1/SRC-3 Is Enhanced by Abl Kinase and Is Required for Its Activity in Cancer Cells.
A. S. Oh, J. T. Lahusen, C. D. Chien, M. P. Fereshteh, X. Zhang, S. Dakshanamurthy, J. Xu, B. L. Kagan, A. Wellstein, and A. T. Riegel (2008)
Mol. Cell. Biol. 28, 6580-6593
   Abstract »    Full Text »    PDF »
Expression of spliced oncogenic Ikaros isoforms in Philadelphia-positive acute lymphoblastic leukemia patients treated with tyrosine kinase inhibitors: implications for a new mechanism of resistance.
I. Iacobucci, A. Lonetti, F. Messa, D. Cilloni, F. Arruga, E. Ottaviani, S. Paolini, C. Papayannidis, P. P. Piccaluga, P. Giannoulia, et al. (2008)
Blood 112, 3847-3855
   Abstract »    Full Text »    PDF »
A Regulatory Circuit Controlling Itch-mediated p73 Degradation by Runx.
D. Levy, N. Reuven, and Y. Shaul (2008)
J. Biol. Chem. 283, 27462-27468
   Abstract »    Full Text »    PDF »
Characteristics of Dasatinib- and Imatinib-Resistant Chronic Myelogenous Leukemia Cells.
S. Okabe, T. Tauchi, and K. Ohyashiki (2008)
Clin. Cancer Res. 14, 6181-6186
   Abstract »    Full Text »    PDF »
The kinase inhibitor dasatinib induces apoptosis in chronic lymphocytic leukemia cells in vitro with preference for a subgroup of patients with unmutated IgVH genes.
A. Veldurthy, M. Patz, S. Hagist, C. P. Pallasch, C.-M. Wendtner, M. Hallek, and G. Krause (2008)
Blood 112, 1443-1452
   Abstract »    Full Text »    PDF »
Small-molecule inhibition and activation-loop trans-phosphorylation of the IGF1 receptor.
J. Wu, W. Li, B. P. Craddock, K. W. Foreman, M. J. Mulvihill, Q.-s. Ji, W. T. Miller, and S. R. Hubbard (2008)
EMBO J. 27, 1985-1994
   Abstract »    Full Text »    PDF »
Therapeutic Options Against BCR-ABL1 T315I-Positive Chronic Myelogenous Leukemia.
A. Quintas-Cardama and J. Cortes (2008)
Clin. Cancer Res. 14, 4392-4399
   Abstract »    Full Text »    PDF »
Association Between Imatinib-Resistant BCR-ABL Mutation-Negative Leukemia and Persistent Activation of LYN Kinase.
J. Wu, F. Meng, L.-Y. Kong, Z. Peng, Y. Ying, W. G. Bornmann, B. G. Darnay, B. Lamothe, H. Sun, M. Talpaz, et al. (2008)
J Natl Cancer Inst 100, 926-939
   Abstract »    Full Text »    PDF »
Current Developments in Genomics and Personalized Health Care: Impact on Public Health.
A. Manamperi (2008)
Asia Pac J Public Health 20, 242-250
   Abstract »    PDF »
Nilotinib.
M. W. Deininger (2008)
Clin. Cancer Res. 14, 4027-4031
   Full Text »    PDF »
Solution Conformations and Dynamics of ABL Kinase-Inhibitor Complexes Determined by NMR Substantiate the Different Binding Modes of Imatinib/Nilotinib and Dasatinib.
N. Vajpai, A. Strauss, G. Fendrich, S. W. Cowan-Jacob, P. W. Manley, S. Grzesiek, and W. Jahnke (2008)
J. Biol. Chem. 283, 18292-18302
   Abstract »    Full Text »    PDF »
Cancers Exhibit a Mutator Phenotype: Clinical Implications.
L. A. Loeb, J. H. Bielas, R. A. Beckman, and I. W. Bodmer (2008)
Cancer Res. 68, 3551-3557
   Abstract »    Full Text »    PDF »
Characterization of compound 584, an Abl kinase inhibitor with lasting effects.
M. Puttini, S. Redaelli, L. Moretti, S. Brussolo, R. H Gunby, L. Mologni, E. Marchesi, L. Cleris, A. Donella-Deana, P. Drueckes, et al. (2008)
Haematologica 93, 653-661
   Abstract »    Full Text »    PDF »
Rational Drug Redesign to Overcome Drug Resistance in Cancer Therapy: Imatinib Moving Target.
A. Fernandez, A. Sanguino, Z. Peng, A. Crespo, E. Ozturk, X. Zhang, S. Wang, W. Bornmann, and G. Lopez-Berestein (2008)
Am. Assoc. Cancer Res. Educ. Book 2008, 589-599
   Abstract »    Full Text »    PDF »
Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic myelogenous leukemia cells.
J. Wu, F. Meng, H. Lu, L. Kong, W. Bornmann, Z. Peng, M. Talpaz, and N. J. Donato (2008)
Blood 111, 3821-3829
   Abstract »    Full Text »    PDF »
Growth inhibition by STI571 in combination with radiation in human chronic myelogenous leukemia K562 cells.
F. Huguet, N. Giocanti, C. Hennequin, M. Croisy, E. Touboul, and V. Favaudon (2008)
Mol. Cancer Ther. 7, 398-406
   Abstract »    Full Text »    PDF »
c-Met Inhibitors with Novel Binding Mode Show Activity against Several Hereditary Papillary Renal Cell Carcinoma-related Mutations.
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. (2008)
J. Biol. Chem. 283, 2675-2683
   Abstract »    Full Text »    PDF »
Concurrent Inhibition of Kit- and Fc{epsilon}RI-Mediated Signaling: Coordinated Suppression of Mast Cell Activation.
B. M. Jensen, M. A. Beaven, S. Iwaki, D. D. Metcalfe, and A. M. Gilfillan (2008)
J. Pharmacol. Exp. Ther. 324, 128-138
   Abstract »    Full Text »    PDF »
Novel Agents in CML Therapy: Tyrosine Kinase Inhibitors and Beyond.
J. V. Melo and C. Chuah (2008)
Hematology 2008, 427-435
   Abstract »    Full Text »    PDF »
Sorafenib Functions to Potently Suppress RET Tyrosine Kinase Activity by Direct Enzymatic Inhibition and Promoting RET Lysosomal Degradation Independent of Proteasomal Targeting.
I. Plaza-Menacho, L. Mologni, E. Sala, C. Gambacorti-Passerini, A. I. Magee, T. P. Links, R. M. W. Hofstra, D. Barford, and C. M. Isacke (2007)
J. Biol. Chem. 282, 29230-29240
   Abstract »    Full Text »    PDF »
Abl Tyrosine Kinase Promotes Dorsal Ruffles but Restrains Lamellipodia Extension during Cell Spreading on Fibronectin.
H. Jin and J. Y.J. Wang (2007)
Mol. Biol. Cell 18, 4143-4154
   Abstract »    Full Text »    PDF »
Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia.
T. O'Hare, C. A. Eide, and M. W. N. Deininger (2007)
Blood 110, 2242-2249
   Abstract »    Full Text »    PDF »
Progressive Thoughts about Progressive Disease.
N. P. Shah (2007)
Clin. Cancer Res. 13, 5229-5231
   Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882