INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity

Asumi Yokota, Shinya Kimura, Satohiro Masuda, Eishi Ashihara, Junya Kuroda, Kiyoshi Sato, Yuri Kamitsuji, Eri Kawata, Yasuyuki Deguchi, Yoshimasa Urasaki, Yasuhito Terui, Martin Ruthardt, Takanori Ueda, Kiyohiko Hatake, Ken Ichi Inui, Taira Maekawa

Research output: Contribution to journalArticle

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Abstract

Central nervous system (CNS) relapse accompanying the prolonged administration of imatinib mesylate has recently become apparent as an impediment to the therapy of Philadelphia chromosome-positive (Ph+) leukemia. CNS relapse may be explained by limited penetration of imatinib mesylate into the cerebrospinal fluid because of the presence of P-glycoprotein at the blood-brain barrier. To overcome imatinib mesylate-resistance mechanisms such as bcr-abl amplification, mutations within the ABL kinase domain, and activation of Lyn, we developed a dual BCR-ABL/Lyn inhibitor, INNO-406 (formerly NS-187), which is 25 to 55 times more potent than imatinib mesylate in vitro and at least 10 times more potent in vivo. The aim of this study was to investigate the efficacy of INNO-406 in treating CNS Ph+ leukemia. We found that INNO-406, like imatinib mesylate, is a substrate for P-glycoprotein. The concentrations of INNO-406 in the CNS were about 10% of those in the plasma. However, this residual concentration was enough to inhibit the growth of Ph+ leukemic cells which expressed not only wildtype but also mutated BCR-ABL in the murine CNS. Furthermore, cyclosporine A, a P-glycoprotein inhibitor, augmented the in vivo activity of INNO-406 against CNS Ph + leukemia. These findings indicate that INNO-406 is a promising agent for the treatment of CNS Ph+ leukemia.

Original languageEnglish
Pages (from-to)306-314
Number of pages9
JournalBlood
Volume109
Issue number1
DOIs
Publication statusPublished - Jan 1 2007

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Growth Inhibitors
Neurology
Protein-Tyrosine Kinases
Cyclosporine
Leukemia
Central Nervous System
P-Glycoprotein
Central Nervous System Agents
Cerebrospinal fluid
Recurrence
Philadelphia Chromosome
Chromosomes
bafetinib
Blood-Brain Barrier
Amplification
Cerebrospinal Fluid
Phosphotransferases
Chemical activation
Imatinib Mesylate
Plasmas

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity. / Yokota, Asumi; Kimura, Shinya; Masuda, Satohiro; Ashihara, Eishi; Kuroda, Junya; Sato, Kiyoshi; Kamitsuji, Yuri; Kawata, Eri; Deguchi, Yasuyuki; Urasaki, Yoshimasa; Terui, Yasuhito; Ruthardt, Martin; Ueda, Takanori; Hatake, Kiyohiko; Inui, Ken Ichi; Maekawa, Taira.

In: Blood, Vol. 109, No. 1, 01.01.2007, p. 306-314.

Research output: Contribution to journalArticle

Yokota, A, Kimura, S, Masuda, S, Ashihara, E, Kuroda, J, Sato, K, Kamitsuji, Y, Kawata, E, Deguchi, Y, Urasaki, Y, Terui, Y, Ruthardt, M, Ueda, T, Hatake, K, Inui, KI & Maekawa, T 2007, 'INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity', Blood, vol. 109, no. 1, pp. 306-314. https://doi.org/10.1182/blood-2006-03-013250
Yokota, Asumi ; Kimura, Shinya ; Masuda, Satohiro ; Ashihara, Eishi ; Kuroda, Junya ; Sato, Kiyoshi ; Kamitsuji, Yuri ; Kawata, Eri ; Deguchi, Yasuyuki ; Urasaki, Yoshimasa ; Terui, Yasuhito ; Ruthardt, Martin ; Ueda, Takanori ; Hatake, Kiyohiko ; Inui, Ken Ichi ; Maekawa, Taira. / INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity. In: Blood. 2007 ; Vol. 109, No. 1. pp. 306-314.
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abstract = "Central nervous system (CNS) relapse accompanying the prolonged administration of imatinib mesylate has recently become apparent as an impediment to the therapy of Philadelphia chromosome-positive (Ph+) leukemia. CNS relapse may be explained by limited penetration of imatinib mesylate into the cerebrospinal fluid because of the presence of P-glycoprotein at the blood-brain barrier. To overcome imatinib mesylate-resistance mechanisms such as bcr-abl amplification, mutations within the ABL kinase domain, and activation of Lyn, we developed a dual BCR-ABL/Lyn inhibitor, INNO-406 (formerly NS-187), which is 25 to 55 times more potent than imatinib mesylate in vitro and at least 10 times more potent in vivo. The aim of this study was to investigate the efficacy of INNO-406 in treating CNS Ph+ leukemia. We found that INNO-406, like imatinib mesylate, is a substrate for P-glycoprotein. The concentrations of INNO-406 in the CNS were about 10{\%} of those in the plasma. However, this residual concentration was enough to inhibit the growth of Ph+ leukemic cells which expressed not only wildtype but also mutated BCR-ABL in the murine CNS. Furthermore, cyclosporine A, a P-glycoprotein inhibitor, augmented the in vivo activity of INNO-406 against CNS Ph + leukemia. These findings indicate that INNO-406 is a promising agent for the treatment of CNS Ph+ leukemia.",
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AU - Yokota, Asumi

AU - Kimura, Shinya

AU - Masuda, Satohiro

AU - Ashihara, Eishi

AU - Kuroda, Junya

AU - Sato, Kiyoshi

AU - Kamitsuji, Yuri

AU - Kawata, Eri

AU - Deguchi, Yasuyuki

AU - Urasaki, Yoshimasa

AU - Terui, Yasuhito

AU - Ruthardt, Martin

AU - Ueda, Takanori

AU - Hatake, Kiyohiko

AU - Inui, Ken Ichi

AU - Maekawa, Taira

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N2 - Central nervous system (CNS) relapse accompanying the prolonged administration of imatinib mesylate has recently become apparent as an impediment to the therapy of Philadelphia chromosome-positive (Ph+) leukemia. CNS relapse may be explained by limited penetration of imatinib mesylate into the cerebrospinal fluid because of the presence of P-glycoprotein at the blood-brain barrier. To overcome imatinib mesylate-resistance mechanisms such as bcr-abl amplification, mutations within the ABL kinase domain, and activation of Lyn, we developed a dual BCR-ABL/Lyn inhibitor, INNO-406 (formerly NS-187), which is 25 to 55 times more potent than imatinib mesylate in vitro and at least 10 times more potent in vivo. The aim of this study was to investigate the efficacy of INNO-406 in treating CNS Ph+ leukemia. We found that INNO-406, like imatinib mesylate, is a substrate for P-glycoprotein. The concentrations of INNO-406 in the CNS were about 10% of those in the plasma. However, this residual concentration was enough to inhibit the growth of Ph+ leukemic cells which expressed not only wildtype but also mutated BCR-ABL in the murine CNS. Furthermore, cyclosporine A, a P-glycoprotein inhibitor, augmented the in vivo activity of INNO-406 against CNS Ph + leukemia. These findings indicate that INNO-406 is a promising agent for the treatment of CNS Ph+ leukemia.

AB - Central nervous system (CNS) relapse accompanying the prolonged administration of imatinib mesylate has recently become apparent as an impediment to the therapy of Philadelphia chromosome-positive (Ph+) leukemia. CNS relapse may be explained by limited penetration of imatinib mesylate into the cerebrospinal fluid because of the presence of P-glycoprotein at the blood-brain barrier. To overcome imatinib mesylate-resistance mechanisms such as bcr-abl amplification, mutations within the ABL kinase domain, and activation of Lyn, we developed a dual BCR-ABL/Lyn inhibitor, INNO-406 (formerly NS-187), which is 25 to 55 times more potent than imatinib mesylate in vitro and at least 10 times more potent in vivo. The aim of this study was to investigate the efficacy of INNO-406 in treating CNS Ph+ leukemia. We found that INNO-406, like imatinib mesylate, is a substrate for P-glycoprotein. The concentrations of INNO-406 in the CNS were about 10% of those in the plasma. However, this residual concentration was enough to inhibit the growth of Ph+ leukemic cells which expressed not only wildtype but also mutated BCR-ABL in the murine CNS. Furthermore, cyclosporine A, a P-glycoprotein inhibitor, augmented the in vivo activity of INNO-406 against CNS Ph + leukemia. These findings indicate that INNO-406 is a promising agent for the treatment of CNS Ph+ leukemia.

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