NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia.
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.
Kimura
Shinya
S
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
Naito
Haruna
H
Segawa
Hidekazu
H
Kuroda
Junya
J
Yuasa
Takeshi
T
Sato
Kiyoshi
K
Yokota
Asumi
A
Kamitsuji
Yuri
Y
Kawata
Eri
E
Ashihara
Eishi
E
Nakaya
Yohei
Y
Naruoka
Haruna
H
Wakayama
Tatsushi
T
Nasu
Kimio
K
Asaki
Tetsuo
T
Niwa
Tomoko
T
Hirabayashi
Kazuko
K
Maekawa
Taira
T
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*
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; C506918:bafetinib