In vivo antiproliferative effect of NS-187, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor, on leukemic cells harbouring Abl kinase domain mutations.
Advanced-phase chronic myeloid leukemia patients treated with imatinib often relapse due to point mutations in the Abl kinase domain. We herein examine the in vitro and in vivo effects of a Bcr-Abl/Lyn dual tyrosine kinase inhibitor, NS-187, on seven mutated Bcr-Abl proteins. NS-187 inhibited both Tyr393-phosphorylated and Tyr393-unphosphorylated Abl, resulting in significant in vitro growth inhibition of cells expressing six of seven mutated Bcr-Abl kinases, though not T315I. Furthermore, NS-187 prolonged the survival of mice injected with leukemic cells expressing all mutated Bcr-Abl tested except T315I, and its efficacy correlated well with its in vitro effects.
Discovery Research Laboratories, Nippon Shinyaku Co., Ltd., 14 Nishinosho Mongucgi-Cho, Minami-Ku, Kyoto 601-8550, Japan.
Haruna
H
Naito
Shinya
S
Kimura
Yohei
Y
Nakaya
Haruna
H
Naruoka
Sachie
S
Kimura
Shinsaku
S
Ito
Tatsushi
T
Wakayama
Taira
T
Maekawa
Kazuko
K
Hirabayashi
D000284:Administration, Oral; D000818:Animals; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016044:Fusion Proteins, bcr-abl / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D010766:Phosphorylation; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D015996:Survival Rate; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; C506918:bafetinib