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0035902180
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Oncogenic kinase signalling
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This is a comprehensive review of the mechanisms by which PTKs are deregulated in human cancers.
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Blume-Jensen P., Hunter T. Oncogenic kinase signalling. Nature. 411:2001;355-365. This is a comprehensive review of the mechanisms by which PTKs are deregulated in human cancers.
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Blume-Jensen, P.1
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Smart drugs: Tyrosine kinase inhibitors in cancer therapy
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Shawver, L.K.1
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0024337144
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Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer
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Levin, W.J.7
Stuart, S.G.8
Udove, J.9
Ullrich, A.10
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0035869407
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Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2
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Slamon D.J., Leyland-Jones B., Shak S., Fuchs H., Paton V., Bajamonde A., Fleming T., Eiermann W., Wolter J., Pegram M., et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 344:2001;783-792.
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N Engl J Med
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Slamon, D.J.1
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Fuchs, H.4
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Bajamonde, A.6
Fleming, T.7
Eiermann, W.8
Wolter, J.9
Pegram, M.10
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5
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0034068319
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Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor
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Ciardiello F., Caputo R., Bianco R., Damiano V., Pomatico G., De Placido S., Bianco A.R., Tortora G. Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res. 6:2000;2053-2063.
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Clin Cancer Res
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Ciardiello, F.1
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Bianco, A.R.7
Tortora, G.8
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0035398631
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Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies
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Hidalgo M., Siu L.L., Nemunaitis J., Rizzo J., Hammond L.A., Takimoto C., Eckhardt S.G., Tolcher A., Britten C.D., Denis L., et al. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol. 19:2001;3267-3279.
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Hidalgo, M.1
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Britten, C.D.9
Denis, L.10
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0034638923
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Mechanisms of angiogenesis and their use in the inhibition of tumor growth and metastasis
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Saaristo A., Karpanen T., Alitalo K. Mechanisms of angiogenesis and their use in the inhibition of tumor growth and metastasis. Oncogene. 19:2000;6122-6129.
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Oncogene
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Saaristo, A.1
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8
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15644363454
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Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors
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Hirota S., Isozaki K., Moriyama Y., Hashimoto K., Nishida T., Ishiguro S., Kawano K., Hanada M., Kurata A., Takeda M., et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 279:1998;577-580.
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Hirota, S.1
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Ishiguro, S.6
Kawano, K.7
Hanada, M.8
Kurata, A.9
Takeda, M.10
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9
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0035810147
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Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia
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A landmark study demonstrating the clinical efficacy of the small-molecule inhibitor STI571, which targets Bcr-Abl, in the treatment of CML.
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Druker B.J., Talpaz M., Resta D.J., Peng B., Buchdunger E., Ford J.M., Lydon N.B., Kantarjian H., Capdeville R., Ohno-Jones S., et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 344:2001;1031-1037. A landmark study demonstrating the clinical efficacy of the small-molecule inhibitor STI571, which targets Bcr-Abl, in the treatment of CML.
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N Engl J Med
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Druker, B.J.1
Talpaz, M.2
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Buchdunger, E.5
Ford, J.M.6
Lydon, N.B.7
Kantarjian, H.8
Capdeville, R.9
Ohno-Jones, S.10
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10
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0030766163
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Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog
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Hubbard S.R. Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog. EMBO J. 16:1997;5572-5581.
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Hubbard, S.R.1
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Active and inactive protein kinases: Structural basis for regulation
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Johnson L.N., Noble M.E.M., Owen D.J. Active and inactive protein kinases: structural basis for regulation. Cell. 85:1996;149-158.
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Cell
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Johnson, L.N.1
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Protein tyrosine kinase structure and function
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Hubbard S.R., Till J.H. Protein tyrosine kinase structure and function. Annu Rev Biochem. 69:2000;373-398.
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Annu Rev Biochem
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Hubbard, S.R.1
Till, J.H.2
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Structural basis for activation of the human lymphocyte kinase Lck upon tyrosine phosphorylation
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Yamaguchi H., Hendrickson W.A. Structural basis for activation of the human lymphocyte kinase Lck upon tyrosine phosphorylation. Nature. 384:1996;484-489.
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Nature
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Yamaguchi, H.1
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0035185571
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Structure and autoregulation of the insulin-like growth factor 1 receptor kinase
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Favelyukis S., Till J.H., Hubbard S.R., Miller W.T. Structure and autoregulation of the insulin-like growth factor 1 receptor kinase. Nat Struct Biol. 8:2001;1058-1063.
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Favelyukis, S.1
Till, J.H.2
Hubbard, S.R.3
Miller, W.T.4
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15
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0028582185
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Crystal structure of the tyrosine kinase domain of the human insulin receptor
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Hubbard S.R., Wei L., Ellis L., Hendrickson W.A. Crystal structure of the tyrosine kinase domain of the human insulin receptor. Nature. 372:1994;746-754.
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Hubbard, S.R.1
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Hendrickson, W.A.4
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16
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0036710123
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Crystal structure of the MuSK tyrosine kinase: Insights into receptor autoregulation
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This structural study provides a second example (after the insulin receptor) of pseudosubstrate inhibition by the kinase activation loop and shows that a helix in the juxtamembrane region of MuSK is poised for protein-protein interactions, perhaps with an inhibitory protein.
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Till J.H., Becerra M., Watty W., Lu Y., Ma Y., Neubert T.A., Burden S.J., Hubbard S.R. Crystal structure of the MuSK tyrosine kinase: insights into receptor autoregulation. Structure. 10:2002;1187-1196. This structural study provides a second example (after the insulin receptor) of pseudosubstrate inhibition by the kinase activation loop and shows that a helix in the juxtamembrane region of MuSK is poised for protein-protein interactions, perhaps with an inhibitory protein.
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(2002)
Structure
, vol.10
, pp. 1187-1196
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Till, J.H.1
Becerra, M.2
Watty, W.3
Lu, Y.4
Ma, Y.5
Neubert, T.A.6
Burden, S.J.7
Hubbard, S.R.8
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17
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0032479283
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Full activation of the platelet-derived growth factor beta-receptor kinase involves multiple events
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Baxter R.M., Secrist J.P., Vaillancourt R.R., Kazlauskas A. Full activation of the platelet-derived growth factor beta-receptor kinase involves multiple events. J Biol Chem. 273:1998;17050-17055.
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Baxter, R.M.1
Secrist, J.P.2
Vaillancourt, R.R.3
Kazlauskas, A.4
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18
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0034086061
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Phosphorylation of tyrosine residues in the kinase domain and juxtamembrane region regulates the biological and catalytic activities of Eph receptors
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This biochemical study provides evidence that phosphorylation of the juxtamembrane tyrosines in the ephrin receptor EphB2 is critical for kinase activation. Mutant EphB2 receptors in which phenylalanine is substituted for tyrosine in the juxtamembrane region do not undergo kinase activation in vitro or in cells.
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Binns K.L., Taylor P.P., Sicheri F., Pawson T., Holland S.J. Phosphorylation of tyrosine residues in the kinase domain and juxtamembrane region regulates the biological and catalytic activities of Eph receptors. Mol Cell Biol. 20:2000;4791-4805. This biochemical study provides evidence that phosphorylation of the juxtamembrane tyrosines in the ephrin receptor EphB2 is critical for kinase activation. Mutant EphB2 receptors in which phenylalanine is substituted for tyrosine in the juxtamembrane region do not undergo kinase activation in vitro or in cells.
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(2000)
Mol Cell Biol
, vol.20
, pp. 4791-4805
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Binns, K.L.1
Taylor, P.P.2
Sicheri, F.3
Pawson, T.4
Holland, S.J.5
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19
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0035929146
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Structural basis for autoinhibition of the Ephb2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region
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This is the first structural study to reveal the mechanism by which the juxtamembrane region of a receptor PTK can function to regulate kinase activity. In the crystal structure of the juxtamembrane region and kinase domain of the ephrin receptor EphB2, the juxtamembrane region kinks α-helix C and hinders the activation loop from assuming its active configuration. Phosphorylation of two juxtamembrane tyrosines is predicted to disrupt these inhibitory interactions, leading to kinase activation.
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Wybenga-Groot L.E., Baskin B., Ong S.H., Tong J., Pawson T., Sicheri F. Structural basis for autoinhibition of the Ephb2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region. Cell. 106:2001;745-757. This is the first structural study to reveal the mechanism by which the juxtamembrane region of a receptor PTK can function to regulate kinase activity. In the crystal structure of the juxtamembrane region and kinase domain of the ephrin receptor EphB2, the juxtamembrane region kinks α-helix C and hinders the activation loop from assuming its active configuration. Phosphorylation of two juxtamembrane tyrosines is predicted to disrupt these inhibitory interactions, leading to kinase activation.
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(2001)
Cell
, vol.106
, pp. 745-757
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Wybenga-Groot, L.E.1
Baskin, B.2
Ong, S.H.3
Tong, J.4
Pawson, T.5
Sicheri, F.6
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20
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0037064087
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Definition of an inhibitory juxtamembrane WW-like domain in the platelet-derived growth factor beta receptor
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This mutagenesis study, along with sequence comparisons, provides evidence that the juxtamembrane region of PDGF receptor subfamily members contains a WW-like domain that inhibits kinase activity in the basal state. Activating mutations in the juxtamembrane region can be rationalized based on a model of the juxtamembrane region as a WW domain.
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Irusta P.M., Luo Y., Bakht O., Lai C.C., Smith S.O., DiMaio D. Definition of an inhibitory juxtamembrane WW-like domain in the platelet-derived growth factor beta receptor. J Biol Chem. 277:2002;38627-38634. This mutagenesis study, along with sequence comparisons, provides evidence that the juxtamembrane region of PDGF receptor subfamily members contains a WW-like domain that inhibits kinase activity in the basal state. Activating mutations in the juxtamembrane region can be rationalized based on a model of the juxtamembrane region as a WW domain.
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(2002)
J Biol Chem
, vol.277
, pp. 38627-38634
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Irusta, P.M.1
Luo, Y.2
Bakht, O.3
Lai, C.C.4
Smith, S.O.5
DiMaio, D.6
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21
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0037138411
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WW and SH3 domains, two different scaffolds to recognize proline-rich ligands
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Macias M.J., Wiesner S., Sudol M. WW and SH3 domains, two different scaffolds to recognize proline-rich ligands. FEBS Lett. 513:2002;30-37.
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FEBS Lett
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Macias, M.J.1
Wiesner, S.2
Sudol, M.3
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22
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0034435424
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Structure of the Tie2 RTK domain: Self-inhibition by the nucleotide binding loop, activation loop, and C-terminal tail
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The structure of the Tie2 kinase domain shows that the C-terminal tail, which contains a site(s) of tyrosine phosphorylation, might partially interfere with substrate binding. In addition, the nucleotide-binding loop is positioned to occlude ATP binding.
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Shewchuk L.M., Hassell A.M., Ellis B., Holmes W.D., Davis R., Horne E.L., Kadwell S.H., McKee D.D., Moore J.T. Structure of the Tie2 RTK domain: self-inhibition by the nucleotide binding loop, activation loop, and C-terminal tail. Struct Fold Des. 8:2000;1105-1113. The structure of the Tie2 kinase domain shows that the C-terminal tail, which contains a site(s) of tyrosine phosphorylation, might partially interfere with substrate binding. In addition, the nucleotide-binding loop is positioned to occlude ATP binding.
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Struct Fold Des
, vol.8
, pp. 1105-1113
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Shewchuk, L.M.1
Hassell, A.M.2
Ellis, B.3
Holmes, W.D.4
Davis, R.5
Horne, E.L.6
Kadwell, S.H.7
McKee, D.D.8
Moore, J.T.9
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23
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0037200045
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Deletion of the carboxy-terminus of Tie2 enhances kinase activity, signaling, and function: Evidence for an autoinhibitory mechanism
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Niu X.L., Peters K.G., Kontos C.D. Deletion of the carboxy-terminus of Tie2 enhances kinase activity, signaling, and function: evidence for an autoinhibitory mechanism. J Biol Chem. 277:2002;31768-31773.
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J Biol Chem
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Niu, X.L.1
Peters, K.G.2
Kontos, C.D.3
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Three-dimensional structure of the tyrosine kinase c-Src
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Xu W., Harrison S.C., Eck M.J. Three-dimensional structure of the tyrosine kinase c-Src. Nature. 385:1997;595-602.
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Nature
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Xu, W.1
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25
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0031034930
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Crystal structure of the Src family tyrosine kinase Hck
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Sicheri F., Moarefi I., Kuriyan J. Crystal structure of the Src family tyrosine kinase Hck. Nature. 385:1997;602-609.
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Nature
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Sicheri, F.1
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26
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0031578579
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The 2.35 Å crystal structure of the inactivated form of chicken Src: A dynamic molecule with multiple regulatory interactions
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Williams J.C., Weijland A., Gonfloni S., Thompson A., Courtneidge S.A., Superti-Furga G., Wierenga R.K. The 2.35 Å crystal structure of the inactivated form of chicken Src: a dynamic molecule with multiple regulatory interactions. J Mol Biol. 274:1997;757-775.
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Williams, J.C.1
Weijland, A.2
Gonfloni, S.3
Thompson, A.4
Courtneidge, S.A.5
Superti-Furga, G.6
Wierenga, R.K.7
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27
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0033152210
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Structural analysis of the lymphocyte-specific kinase Lck in complex with non-selective and Src family selective kinase inhibitors
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Zhu X., Kim J.L., Newcomb J.R., Rose P.E., Stover D.R., Toledo L.M., Zhao H., Morgenstern K.A. Structural analysis of the lymphocyte-specific kinase Lck in complex with non-selective and Src family selective kinase inhibitors. Struct Fold Des. 7:1999;651-661.
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Struct Fold Des
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Zhu, X.1
Kim, J.L.2
Newcomb, J.R.3
Rose, P.E.4
Stover, D.R.5
Toledo, L.M.6
Zhao, H.7
Morgenstern, K.A.8
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28
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0033001789
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Crystal structures of c-Src reveal features of its autoinhibitory mechanism
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Xu W., Doshi A., Lei M., Eck M.J., Harrison S.C. Crystal structures of c-Src reveal features of its autoinhibitory mechanism. Mol Cell. 3:1999;629-638.
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Mol Cell
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Xu, W.1
Doshi, A.2
Lei, M.3
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Harrison, S.C.5
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29
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0033063429
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Crystal structure of Hck in complex with a Src family-selective tyrosine kinase inhibitor
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Schindler T., Sicheri F., Pico A., Gazit A., Levitzki A., Kuriyan J. Crystal structure of Hck in complex with a Src family-selective tyrosine kinase inhibitor. Mol Cell. 3:1999;639-648.
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Mol Cell
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Schindler, T.1
Sicheri, F.2
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Kuriyan, J.6
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Structures of Src-family tyrosine kinases
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Sicheri F., Kuriyan J. Structures of Src-family tyrosine kinases. Curr Opin Struct Biol. 7:1997;777-785.
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Kuriyan, J.2
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Cycling, stressed-out and nervous: Cellular functions of c-Abl
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Van Etten R.A. Cycling, stressed-out and nervous: cellular functions of c-Abl. Trends Cell Biol. 9:1999;179-186.
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Van Etten, R.A.1
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0037169351
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Autoinhibition of c-Abl
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This biochemical study provides evidence that Abl is autoregulated through interactions between its unique N-terminal region and the SH3 and tyrosine kinase domains. The previous consensus was that a cellular inhibitory protein was involved in maintaining the repressed state of Abl.
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Pluk H., Dorey K., Superti-Furga G. Autoinhibition of c-Abl. Cell. 108:2002;247-259. This biochemical study provides evidence that Abl is autoregulated through interactions between its unique N-terminal region and the SH3 and tyrosine kinase domains. The previous consensus was that a cellular inhibitory protein was involved in maintaining the repressed state of Abl.
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Cell
, vol.108
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Pluk, H.1
Dorey, K.2
Superti-Furga, G.3
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33
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0034665713
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Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase
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The structure of the tyrosine kinase domain of Abl in complex with a variant of the small-molecule inhibitor STI571 establishes the mode of inhibition of this clinically relevant inhibitor. This study provides an example of 'conformational specificity', in which interactions with conserved sidechains nevertheless contribute to specificity through differential positioning of the conserved residues. The unphosphorylated form of Abl is shown to be more susceptible to inhibition by STI571 than the phosphorylated, activated form.
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Schindler T., Bornmann W., Pellicena P., Miller W.T., Clarkson B., Kuriyan J. Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science. 289:2000;1938-1942. The structure of the tyrosine kinase domain of Abl in complex with a variant of the small-molecule inhibitor STI571 establishes the mode of inhibition of this clinically relevant inhibitor. This study provides an example of 'conformational specificity', in which interactions with conserved sidechains nevertheless contribute to specificity through differential positioning of the conserved residues. The unphosphorylated form of Abl is shown to be more susceptible to inhibition by STI571 than the phosphorylated, activated form.
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Science
, vol.289
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Schindler, T.1
Bornmann, W.2
Pellicena, P.3
Miller, W.T.4
Clarkson, B.5
Kuriyan, J.6
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Domain interactions in protein tyrosine kinase Csk
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Sondhi D., Cole P.A. Domain interactions in protein tyrosine kinase Csk. Biochemistry. 38:1999;11147-11155.
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Biochemistry
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Sondhi, D.1
Cole, P.A.2
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35
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0037177880
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Structure of the carboxyl-terminal Src kinase, Csk
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The crystal structure of the SH3, SH2 and kinase domains of CSK shows a domain arrangement unlike that in Src, with both the SH2 and SH3 domains interacting with the N-terminal lobe of the kinase domain. As opposed to Src, in CSK the interactions of the SH2 and SH3 domains with the kinase domain, α-helix C in particular, are stimulatory.
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Ogawa A., Takayama Y., Sakai H., Chong K.T., Takeuchi S., Nakagawa A., Nada S., Okada M., Tsukihara T. Structure of the carboxyl-terminal Src kinase, Csk. J Biol Chem. 277:2002;14351-14354. The crystal structure of the SH3, SH2 and kinase domains of CSK shows a domain arrangement unlike that in Src, with both the SH2 and SH3 domains interacting with the N-terminal lobe of the kinase domain. As opposed to Src, in CSK the interactions of the SH2 and SH3 domains with the kinase domain, α-helix C in particular, are stimulatory.
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(2002)
J Biol Chem
, vol.277
, pp. 14351-14354
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Ogawa, A.1
Takayama, Y.2
Sakai, H.3
Chong, K.T.4
Takeuchi, S.5
Nakagawa, A.6
Nada, S.7
Okada, M.8
Tsukihara, T.9
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36
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0033555270
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Structure of the protein tyrosine kinase domain of C-terminal Src kinase (CSK) in complex with staurosporine
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Lamers M.B., Antson A.A., Hubbard R.E., Scott R.K., Williams D.H. Structure of the protein tyrosine kinase domain of C-terminal Src kinase (CSK) in complex with staurosporine. J Mol Biol. 285:1999;713-725.
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J Mol Biol
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Lamers, M.B.1
Antson, A.A.2
Hubbard, R.E.3
Scott, R.K.4
Williams, D.H.5
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37
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0033636260
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A peptide library approach identifies a specific inhibitor for the ZAP-70 protein tyrosine kinase
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Nishikawa K., Sawasdikosol S., Fruman D.A., Lai J., Songyang Z., Burakoff S.J., Yaffe M.B., Cantley L.C. A peptide library approach identifies a specific inhibitor for the ZAP-70 protein tyrosine kinase. Mol Cell. 6:2000;969-974.
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Mol Cell
, vol.6
, pp. 969-974
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Nishikawa, K.1
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Fruman, D.A.3
Lai, J.4
Songyang, Z.5
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2.2 Å refined crystal structure of the catalytic subunit of cAMP-dependent protein kinase complexed with MnATP and a peptide inhibitor
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Zheng J., Trafny E.A., Knighton D.R., Xuong N.H., Taylor S.S., Ten Eyck L.F., Sowadski J.M. 2.2 Å refined crystal structure of the catalytic subunit of cAMP-dependent protein kinase complexed with MnATP and a peptide inhibitor. Acta Crystallogr. D49:1993;362-365.
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The crystal structure of a phosphorylase kinase peptide substrate complex: Kinase substrate recognition
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Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors
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43
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0032531929
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Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain
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Mohammadi M., Froum S., Hamby J.M., Schroeder M.C., Panek R.L., Liu G.H., Eliseenkova A.V., Green D., Schlessinger J., Hubbard S.R. Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain. EMBO J. 17:1998;5896-5904.
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44
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Structure of the EGF receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor
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in press. This is the first report of a crystal structure of the EGF receptor kinase domain, alone and in complex with Tarceva, a 4-anilinoquinazoline inhibitor. The structure shows that the kinase domain is in an active state, without phosphorylation of an activation loop tyrosine, which is consistent with previous biochemical results.
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Stamos J, Sliwkowski MX, Eigenbrot C: Structure of the EGF receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J Biol Chem 2002, in press. This is the first report of a crystal structure of the EGF receptor kinase domain, alone and in complex with Tarceva, a 4-anilinoquinazoline inhibitor. The structure shows that the kinase domain is in an active state, without phosphorylation of an activation loop tyrosine, which is consistent with previous biochemical results.
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J Biol Chem 2002
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Stamos, J.1
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Eigenbrot, C.3
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Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and Imatinib (STI-571)
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Crystal structures of the Abl kinase domain with bona fide STI571, as well as with an inhibitor of the pyrido-pyrimidine class, reveal different modes of interaction between the compounds and the unphosphorylated activation loop. The pyrido-pyrimidine compound inhibits both unphosphorylated and phosphorylated forms of Abl equally well, which might explain its tenfold higher potency over STI571.
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Nagar B., Bornmann W.G., Pellicena P., Schindler T., Veach D.R., Miller W.T., Clarkson B., Kuriyan J. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and Imatinib (STI-571). Cancer Res. 62:2002;4236-4243. Crystal structures of the Abl kinase domain with bona fide STI571, as well as with an inhibitor of the pyrido-pyrimidine class, reveal different modes of interaction between the compounds and the unphosphorylated activation loop. The pyrido-pyrimidine compound inhibits both unphosphorylated and phosphorylated forms of Abl equally well, which might explain its tenfold higher potency over STI571.
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Nagar, B.1
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Kuriyan, J.8
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46
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Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative
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Lydon, N.B.7
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47
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0037199996
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Analysis of the structural basis of specificity of inhibition of the Abl kinase by STI571
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This mutagenesis study tests the effects of various Abl mutations on inhibition by STI571 and ATP binding. The Thr315→Ile mutation found in relapsed CML patients shows a marked decrease in STI571 susceptibility without loss of ATP binding, as would be predicted. The study reveals additional mutations that confer STI571 insensitivity while maintaining Abl catalytic activity.
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Corbin A.S., Buchdunger E., Pascal F., Druker B.J. Analysis of the structural basis of specificity of inhibition of the Abl kinase by STI571. J Biol Chem. 277:2002;32214-32219. This mutagenesis study tests the effects of various Abl mutations on inhibition by STI571 and ATP binding. The Thr315→Ile mutation found in relapsed CML patients shows a marked decrease in STI571 susceptibility without loss of ATP binding, as would be predicted. The study reveals additional mutations that confer STI571 insensitivity while maintaining Abl catalytic activity.
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Corbin, A.S.1
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Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification
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Gorre, M.E.1
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Paquette, R.5
Rao, P.N.6
Sawyers, C.L.7
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