title: A non-ATP-competitive inhibitor of BCR-ABL overrides imatinib resistance.
abstract: Imatinib, which is an inhibitor of the BCR-ABL tyrosine kinase, has been a remarkable success for the treatment of Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemias (CMLs). However, a significant proportion of patients chronically treated with imatinib develop resistance because of the acquisition of mutations in the kinase domain of BCR-ABL. Mutations occur at residues directly implicated in imatinib binding or, more commonly, at residues important for the ability of the kinase to adopt the specific closed (inactive) conformation to which imatinib binds. In our quest to develop new BCR-ABL inhibitors, we chose to target regions outside the ATP-binding site of this enzyme because these compounds offer the potential to be unaffected by mutations that make CML cells resistant to imatinib. Here we describe the activity of one compound, ON012380, that can specifically inhibit BCR-ABL and induce cell death of Ph+ CML cells at a concentration of <10 nM. Kinetic studies demonstrate that this compound is not ATP-competitive but is substrate-competitive and works synergistically with imatinib in wild-type BCR-ABL inhibition. More importantly, ON012380 was found to induce apoptosis of all of the known imatinib-resistant mutants at concentrations of <10 nM concentration in vitro and cause regression of leukemias induced by i.v. injection of 32Dcl3 cells expressing the imatinib-resistant BCR-ABL isoform T315I. Daily i.v. dosing for up to 3 weeks with a >100 mg/kg concentration of this agent is well tolerated in rodents, without any hematotoxicity.
authors.affiliation: The Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 North Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Kiranmai
authors.initials: K
authors.lastname: Gumireddy
authors.forename: Stacey J
authors.initials: SJ
authors.lastname: Baker
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Cosenza
authors.forename: Premila
authors.initials: P
authors.lastname: John
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Kang
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Robell
authors.forename: M V Ramana
authors.initials: MV
authors.lastname: Reddy
authors.forename: E Premkumar
authors.initials: EP
authors.lastname: Reddy
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D001549:Benzamides; D001555:Benzene Derivatives / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D016923:Cell Death; D019008:Drug Resistance, Neoplasm; D005260:Female; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009154:Mutation; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D001555:Benzene Derivatives; C499758:ON012380; D010879:Piperazines; D011743:Pyrimidines; D011994:Recombinant Proteins; D000068877:Imatinib Mesylate; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl