title: NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia.
abstract: Although the Abelson (Abl) tyrosine kinase inhibitor imatinib mesylate has improved the treatment of breakpoint cluster region-Abl (Bcr-Abl)-positive leukemia, resistance is often reported in patients with advanced-stage disease. Although several Src inhibitors are more effective than imatinib and simultaneously inhibit Lyn, whose overexpression is associated with imatinib resistance, these inhibitors are less specific than imatinib. We have identified a specific dual Abl-Lyn inhibitor, NS-187 (elsewhere described as CNS-9), which is 25 to 55 times more potent than imatinib in vitro. NS-187 is also at least 10 times as effective as imatinib in suppressing the growth of Bcr-Abl-bearing tumors and markedly extends the survival of mice bearing such tumors. The inhibitory effect of NS-187 extends to 12 of 13 Bcr-Abl proteins with mutations in their kinase domain but not to T315I. NS-187 also inhibits Lyn without affecting the phosphorylation of Src, Blk, or Yes. These results suggest that NS-187 may be a potentially valuable novel agent to combat imatinib-resistant Philadelphia-positive (Ph+) leukemia.
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. shkimu@kuhp.kyoto-u.ac.jp
authors.forename: Shinya
authors.initials: S
authors.lastname: Kimura
authors.forename: Haruna
authors.initials: H
authors.lastname: Naito
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Segawa
authors.forename: Junya
authors.initials: J
authors.lastname: Kuroda
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yuasa
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Sato
authors.forename: Asumi
authors.initials: A
authors.lastname: Yokota
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kamitsuji
authors.forename: Eri
authors.initials: E
authors.lastname: Kawata
authors.forename: Eishi
authors.initials: E
authors.lastname: Ashihara
authors.forename: Yohei
authors.initials: Y
authors.lastname: Nakaya
authors.forename: Haruna
authors.initials: H
authors.lastname: Naruoka
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Wakayama
authors.forename: Kimio
authors.initials: K
authors.lastname: Nasu
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Asaki
authors.forename: Tomoko
authors.initials: T
authors.lastname: Niwa
authors.forename: Kazuko
authors.initials: K
authors.lastname: Hirabayashi
authors.forename: Taira
authors.initials: T
authors.lastname: Maekawa
mesh_terms: D000818:Animals; D001549:Benzamides; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D016313:Genes, abl / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D007938:Leukemia / Q000188:drug therapy*; D051379:Mice; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D019061:src-Family Kinases / Q000187:drug effects*
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; C506918:bafetinib