title: Allosteric inhibition enhances the efficacy of ABL kinase inhibitors to target unmutated BCR-ABL and BCR-ABL-T315I.
abstract: BACKGROUND
  Chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (Ph + ALL) are caused by the t(9;22), which fuses BCR to ABL resulting in deregulated ABL-tyrosine kinase activity. The constitutively activated BCR/ABL-kinase "escapes" the auto-inhibition mechanisms of c-ABL, such as allosteric inhibition. The ABL-kinase inhibitors (AKIs) Imatinib, Nilotinib or Dasatinib, which target the ATP-binding site, are effective in Ph + leukemia. Another molecular therapy approach targeting BCR/ABL restores allosteric inhibition. Given the fact that all AKIs fail to inhibit BCR/ABL harboring the 'gatekeeper' mutation T315I, we investigated the effects of AKIs in combination with the allosteric inhibitor GNF2 in Ph + leukemia.
  
  
  METHODS
  The efficacy of this approach on the leukemogenic potential of BCR/ABL was studied in Ba/F3 cells, primary murine bone marrow cells, and untransformed Rat-1 fibroblasts expressing BCR/ABL or BCR/ABL-T315I as well as in patient-derived long-term cultures (PDLTC) from Ph + ALL-patients.
  
  
  RESULTS
  Here, we show that GNF-2 increased the effects of AKIs on unmutated BCR/ABL. Interestingly, the combination of Dasatinib and GNF-2 overcame resistance of BCR/ABL-T315I in all models used in a synergistic manner.
  
  
  CONCLUSIONS
  Our observations establish a new approach for the molecular targeting of BCR/ABL and its resistant mutants using a combination of AKIs and allosteric inhibitors.
authors.affiliation: Department of Hematology, Goethe University, Frankfurt, Germany.
authors.forename: Afsar Ali
authors.initials: AA
authors.lastname: Mian
authors.forename: Anna
authors.initials: A
authors.lastname: Metodieva
authors.forename: Susanne
authors.initials: S
authors.lastname: Badura
authors.forename: Mamduh
authors.initials: M
authors.lastname: Khateb
authors.forename: Nili
authors.initials: N
authors.lastname: Ruimi
authors.forename: Yousef
authors.initials: Y
authors.lastname: Najajreh
authors.forename: Oliver Gerhard
authors.initials: OG
authors.lastname: Ottmann
authors.forename: Jamal
authors.initials: J
authors.lastname: Mahajna
authors.forename: Martin
authors.initials: M
authors.lastname: Ruthardt
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D000069439:Dasatinib; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics*; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics; D051379:Mice; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C508526:GNF-2 compound; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib