title: Novel pyrrolo-1,5-benzoxazepine compounds display significant activity against resistant chronic myeloid leukaemia cells in vitro, in ex vivo patient samples and in vivo.
abstract: BACKGROUND
  Imatinib is a direct and potent inhibitor of the constitutively active tyrosine kinase, breakpoint cluster region-Abelson (Bcr-Abl), which is central to the pathogenesis of chronic myeloid leukaemia (CML) patients. As such, imatinib has become the front-line treatment for CML patients. However, the recent emergence of imatinib resistance, commonly associated with point mutations within the kinase domain, has led to the search for alternative drug treatments and combination therapies for CML.
  
  
  METHODS
  In this report, we analyse the effects of representative members of the novel pro-apoptotic microtubule depolymerising pyrrolo-1,5-benzoxazepines or PBOX compounds on chemotherapy-refractory CML cells using a series of Bcr-Abl mutant cell lines, clinical ex vivo patient samples and an in vivo mouse model.
  
  
  RESULTS
  The PBOX compounds potently reduce cell viability in cells expressing the E225K and H396P mutants as well as the highly resistant T315I mutant. The PBOX compounds also induce apoptosis in primary CML samples including those resistant to imatinib. We also show for the first time, the in vivo efficacy of the pro-apoptotic PBOX compound, PBOX-6, in a CML mouse model of the T315I Bcr-Abl mutant.
  
  
  CONCLUSIONS
  Results from this study highlight the potential of these novel series of PBOX compounds as an effective therapy against CML.
authors.affiliation: School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland. brights@tcd.ie
authors.forename: S A
authors.initials: SA
authors.lastname: Bright
authors.forename: A M
authors.initials: AM
authors.lastname: McElligott
authors.forename: J W
authors.initials: JW
authors.lastname: O'Connell
authors.forename: L
authors.initials: L
authors.lastname: O'Connor
authors.forename: P
authors.initials: P
authors.lastname: Carroll
authors.forename: G
authors.initials: G
authors.lastname: Campiani
authors.forename: M W
authors.initials: MW
authors.lastname: Deininger
authors.forename: E
authors.initials: E
authors.lastname: Conneally
authors.forename: M
authors.initials: M
authors.lastname: Lawler
authors.forename: D C
authors.initials: DC
authors.lastname: Williams
authors.forename: D M
authors.initials: DM
authors.lastname: Zisterer
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D016313:Genes, abl / Q000235:genetics; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009154:Mutation; D010077:Oxazepines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D010077:Oxazepines; D011758:Pyrroles; C418868:PBOX-6
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