Biological Crystallography Structural Biology Contributions to the Discovery of Drugs to Treat Chronic Myelogenous Leukaemia

Chronic myelogenous leukaemia (CML) results from the Bcr-Abl oncoprotein, which has a constitutively activated Abl tyrosine kinase domain. Although most chronic phase CML patients treated with imatinib as first-line therapy maintain excellent durable responses, patients who have progressed to advanced-stage CML frequently fail to respond or lose their response to therapy owing to the emergence of drug-resistant mutants of the protein. More than 40 such point mutations have been observed in imatinib-resistant patients. The crystal structures of wild-type and mutant Abl kinase in complex with imatinib and other small-molecule Abl inhibitors were determined, with the aim of understanding the molecular basis of resistance and to aid in the design and optimization of inhibitors active against the resistance mutants. These results are presented in a way which illustrates the approaches used to generate multiple structures, the type of information that can be gained and the way that this information is used to support drug discovery.

[1]  Wolfgang Jahnke,et al.  Solution Conformations and Dynamics of ABL Kinase-Inhibitor Complexes Determined by NMR Substantiate the Different Binding Modes of Imatinib/Nilotinib and Dasatinib*♦ , 2008, Journal of Biological Chemistry.

[2]  J. Radich,et al.  Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. , 2008, Blood.

[3]  K. Bhalla,et al.  Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. , 2007, Blood.

[4]  M. Deininger,et al.  Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. , 2007, Blood.

[5]  Junia V. Melo,et al.  Chronic myeloid leukaemia as a model of disease evolution in human cancer , 2007, Nature Reviews Cancer.

[6]  Francisco Cervantes,et al.  Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. , 2006, Blood.

[7]  T. Kinoshita,et al.  Structure of human Fyn kinase domain complexed with staurosporine. , 2006, Biochemical and biophysical research communications.

[8]  N. Gray,et al.  Rational design of inhibitors that bind to inactive kinase conformations , 2006, Nature chemical biology.

[9]  K. Bhalla,et al.  Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. , 2006, The New England journal of medicine.

[10]  B. Druker.  Circumventing resistance to kinase-inhibitor therapy. , 2006, The New England journal of medicine.

[11]  J. Mestan,et al.  AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL , 2006, British Journal of Cancer.

[12]  John Kuriyan,et al.  A Src-Like Inactive Conformation in the Abl Tyrosine Kinase Domain , 2006, PLoS biology.

[13]  Oliver Hantschel,et al.  Organization of the SH3-SH2 unit in active and inactive forms of the c-Abl tyrosine kinase. , 2006, Molecular cell.

[14]  Daniel K. Treiber,et al.  Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680. , 2006, Cancer research.

[15]  J. Mestan,et al.  Advances in the structural biology, design and clinical development of Bcr-Abl kinase inhibitors for the treatment of chronic myeloid leukaemia. , 2005, Biochimica et biophysica acta.

[16]  J. Mestan,et al.  Molecular Interactions between the Highly Selective pan-Bcr-Abl Inhibitor, AMN107, and the Tyrosine Kinase Domain of Abl. , 2005 .

[17]  D. Fabbro,et al.  The crystal structure of a c-Src complex in an active conformation suggests possible steps in c-Src activation. , 2005, Structure.

[18]  R. Ren,et al.  Mechanisms of BCR–ABL in the pathogenesis of chronic myelogenous leukaemia , 2005, Nature Reviews Cancer.

[19]  Donna Neuberg,et al.  Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. , 2005, Cancer cell.

[20]  Stephen K Burley,et al.  A Novel Mode of Gleevec Binding Is Revealed by the Structure of Spleen Tyrosine Kinase* , 2004, Journal of Biological Chemistry.

[21]  Ram Thaimattam,et al.  3D-QSAR CoMFA, CoMSIA studies on substituted ureas as Raf-1 kinase inhibitors and its confirmation with structure-based studies. , 2004, Bioorganic & medicinal chemistry.

[22]  J. Mestan,et al.  Urea derivatives of STI571 as inhibitors of Bcr-Abl and PDGFR kinases. , 2004, Bioorganic & medicinal chemistry letters.

[23]  Eugene C. Petrella,et al.  The Three-dimensional Structure of the ZAP-70 Kinase Domain in Complex with Staurosporine , 2004, Journal of Biological Chemistry.

[24]  K. Wilson,et al.  Structural Basis for the Autoinhibition and STI-571 Inhibition of c-Kit Tyrosine Kinase* , 2004, Journal of Biological Chemistry.

[25]  D. Barford,et al.  Mechanism of Activation of the RAF-ERK Signaling Pathway by Oncogenic Mutations of B-RAF , 2004, Cell.

[26]  J. Mestan,et al.  Advances in the structural biology, design and clinical development of VEGF-R kinase inhibitors for the treatment of angiogenesis. , 2004, Biochimica et biophysica acta.

[27]  J. Mestan,et al.  Imatinib (STI571) resistance in chronic myelogenous leukemia: molecular basis of the underlying mechanisms and potential strategies for treatment. , 2004, Mini reviews in medicinal chemistry.

[28]  F. Lu,et al.  The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. , 2004, Molecular cell.

[29]  Gerard J Kleywegt,et al.  Application and limitations of X-ray crystallographic data in structure-based ligand and drug design. , 2003, Angewandte Chemie.

[30]  G. Superti-Furga,et al.  Structural Basis for the Autoinhibition of c-Abl Tyrosine Kinase , 2003, Cell.

[31]  G. Daley,et al.  Mechanisms of Autoinhibition and STI-571/Imatinib Resistance Revealed by Mutagenesis of BCR-ABL , 2003, Cell.

[32]  D. Fabbro,et al.  Imatinib: a selective tyrosine kinase inhibitor. , 2002, European journal of cancer.

[33]  J. Kuriyan,et al.  Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. , 2002, Cancer cell.

[34]  Alex Matter,et al.  Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug , 2002, Nature Reviews Drug Discovery.

[35]  L. Tong,et al.  Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site , 2002, Nature Structural Biology.

[36]  A. Pautsch,et al.  Crystal structure of bisphosphorylated IGF-1 receptor kinase: insight into domain movements upon kinase activation. , 2001, Structure.

[37]  K. Altmann,et al.  Anticancer Agents: Frontiers in Cancer Chemotherapy , 2001 .

[38]  P. Furet,et al.  STI571: A New Treatment Modality for CML? , 2001 .

[39]  P. N. Rao,et al.  Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification , 2001, Science.

[40]  John Kuriyan,et al.  Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). , 2001, Cancer research.

[41]  P. Seeburg,et al.  Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. , 2000, Science.

[42]  L. Toledo,et al.  Structural analysis of the lymphocyte-specific kinase Lck in complex with non-selective and Src family selective kinase inhibitors. , 2000, Structure.

[43]  S. Harrison,et al.  Crystal structures of c-Src reveal features of its autoinhibitory mechanism. , 1999, Molecular cell.

[44]  A. Vagin,et al.  MOLREP: an Automated Program for Molecular Replacement , 1997 .

[45]  S. Hubbard,et al.  Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors. , 1997, Science.

[46]  S. Hubbard,et al.  Crystal structure of the tyrosine kinase domain of the human insulin receptor , 1994, Nature.

[47]  M. Gerretsen,et al.  L1210 cells selected for resistance to methoxymorpholinyl doxorubicin appear specifically resistant to this class of morpholinyl derivatives , 1994 .

[48]  J. Thornton,et al.  PROCHECK: a program to check the stereochemical quality of protein structures , 1993 .

[49]  J. Zou,et al.  Improved methods for building protein models in electron density maps and the location of errors in these models. , 1991, Acta crystallographica. Section A, Foundations of crystallography.

[50]  P. Sperryn,et al.  Blood. , 1989, British journal of sports medicine.

[51]  A. Chadli.  THE CANCER CELL , 1924, La Presse medicale.