2f4j Citations

Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680.

Abstract

We present a high-resolution (2.0 A) 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 His(396)Pro 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.

Reviews - 2f4j mentioned but not cited (2)

  1. SPLINTS: small-molecule protein ligand interface stabilizers. Fischer ES, Park E, Eck MJ, Thomä NH. Curr. Opin. Struct. Biol. 37 115-122 (2016)
  2. SPLINTS: small-molecule protein ligand interface stabilizers. Fischer ES, Park E, Eck MJ, Thomä NH. Curr. Opin. Struct. Biol. 37 115-122 (2016)

Articles - 2f4j mentioned but not cited (4)

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Reviews citing this publication (82)

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  5. Applying the discovery of the Philadelphia chromosome. Sherbenou DW, Druker BJ. J. Clin. Invest. 117 2067-2074 (2007)
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  7. Part II: management of resistance to imatinib in chronic myeloid leukaemia. Apperley JF. Lancet Oncol. 8 1116-1128 (2007)
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  13. Optimizing therapy of chronic myeloid leukemia. Deininger MW. Exp. Hematol. 35 144-154 (2007)
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  15. New Bcr-Abl inhibitors in chronic myeloid leukemia: keeping resistance in check. O'Hare T, Eide CA, Deininger MW. Expert Opin Investig Drugs 17 865-878 (2008)
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  50. Molecular mechanisms of drug resistance in tyrosine kinases cAbl and cKit. DiNitto JP, Wu JC. Crit. Rev. Biochem. Mol. Biol. 46 295-309 (2011)
  51. New drugs for chronic myelogenous leukemia. Santos FP, Quintás-Cardama A. Curr Hematol Malig Rep 6 96-103 (2011)
  52. Mechanisms of drug resistance in kinases. Barouch-Bentov R, Sauer K. Expert Opin Investig Drugs 20 153-208 (2011)
  53. Current treatment options for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Stock W. Leuk. Lymphoma 51 188-198 (2010)
  54. Aurora kinase inhibitors as anticancer molecules. Katayama H, Sen S. Biochim. Biophys. Acta 1799 829-839 (2010)
  55. NCI First International Workshop on The Biology, Prevention and Treatment of Relapse after Allogeneic Hematopoietic Cell Transplantation: report from the committee on prevention of relapse following allogeneic cell transplantation for hematologic malignancies. Alyea EP, DeAngelo DJ, Moldrem J, Pagel JM, Przepiorka D, Sadelin M, Young JW, Giralt S, Bishop M, Riddell S. Biol. Blood Marrow Transplant. 16 1037-1069 (2010)
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  57. Hypothesis: upfront use of ABL kinase inhibitor combination, either simultaneously or sequentially, in high-risk Ph+ leukemias? Carella AM. Ann. Hematol. 89 531-533 (2010)
  58. Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias. Moore AS, Blagg J, Linardopoulos S, Pearson AD. Leukemia 24 671-678 (2010)
  59. Use of dasatinib and nilotinib in imatinib-resistant chronic myeloid leukemia: translating preclinical findings to clinical practice. DeAngelo DJ, Attar EC. Leuk. Lymphoma 51 363-375 (2010)
  60. Cancer driver mutations in protein kinase genes. Torkamani A, Verkhivker G, Schork NJ. Cancer Lett. 281 117-127 (2009)
  61. Advances in Aurora kinase inhibitor patents. Coumar MS, Cheung CH, Chang JY, Hsieh HP. Expert Opin Ther Pat 19 321-356 (2009)
  62. Structural biology contributions to tyrosine kinase drug discovery. Cowan-Jacob SW, Möbitz H, Fabbro D. Curr. Opin. Cell Biol. 21 280-287 (2009)
  63. Targeting cancer with small molecule kinase inhibitors. Zhang J, Yang PL, Gray NS. Nat. Rev. Cancer 9 28-39 (2009)
  64. Aurora kinases as targets for cancer therapy. Mountzios G, Terpos E, Dimopoulos MA. Cancer Treat. Rev. 34 175-182 (2008)
  65. Abl tyrosine kinase inhibitors for overriding Bcr-Abl/T315I: from the second to third generation. Tanaka R, Kimura S. Expert Rev Anticancer Ther 8 1387-1398 (2008)
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  68. The genetics of cancer survivorship. Allan JM. Hematol. Oncol. Clin. North Am. 22 257-69 (2008)
  69. State-of-the-art in the treatment of chronic myeloid leukaemia. Milojkovic D, Apperley J. Curr Opin Oncol 20 112-121 (2008)
  70. Emerging therapeutic options for Philadelphia-positive acute lymphocytic leukemia. Alvarado Y, Apostolidou E, Swords R, Giles FJ. Expert Opin Emerg Drugs 12 165-179 (2007)
  71. Stem cell and kinase activity-independent pathway in resistance of leukaemia to BCR-ABL kinase inhibitors. Li S, Li D. J. Cell. Mol. Med. 11 1251-1262 (2007)
  72. Strategies for overcoming imatinib resistance in chronic myeloid leukemia. Kujawski L, Talpaz M. Leuk. Lymphoma 48 2310-2322 (2007)
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  76. Flying under the radar: the new wave of BCR-ABL inhibitors. Quintás-Cardama A, Kantarjian H, Cortes J. Nat Rev Drug Discov 6 834-848 (2007)
  77. Applying the discovery of the Philadelphia chromosome. Sherbenou DW, Druker BJ. J. Clin. Invest. 117 2067-2074 (2007)
  78. Treatment for chronic myelogenous leukemia: the long road to imatinib. Hunter T. J. Clin. Invest. 117 2036-2043 (2007)
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  81. New light for science: synchrotron radiation in structural medicine. Sorensen TL, McAuley KE, Flaig R, Duke EM. Trends Biotechnol. 24 500-508 (2006)
  82. Emerging drugs in chronic myelogenous leukaemia. Bocchia M, Forconi F, Lauria F. Expert Opin Emerg Drugs 11 651-664 (2006)

Articles citing this publication (78)

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  38. PHA-680626 exhibits anti-proliferative and pro-apoptotic activity on Imatinib-resistant chronic myeloid leukemia cell lines and primary CD34+ cells by inhibition of both Bcr-Abl tyrosine kinase and Aurora kinases. Gontarewicz A, Balabanov S, Keller G, Panse J, Schafhausen P, Bokemeyer C, Fiedler W, Moll J, Brümmendorf TH. Leuk. Res. 32 1857-1865 (2008)
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