[INNO-406 suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity]
>>Blood, 1 January 2007, Vol. 109, No. 1, pp. 306-314.
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 Yokota1, Shinya Kimura1,, Satohiro Masuda2, Eishi Ashihara1, Junya Kuroda1,3, Kiyoshi Sato1, Yuri Kamitsuji1,3, Eri Kawata1,3, Yasuyuki Deguchi1,4, Yoshimasa Urasaki5, Yasuhito Terui6, Martin Ruthardt7, Takanori Ueda5, Kiyohiko Hatake6, Ken-ichi Inui2, and Taira Maekawa1
1 Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan; 2 Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan; 3 Department of Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; 4 Department of Gastroenterology and Hematology, Shiga University of Medical Science, Shiga, Japan; 5 First Department of Internal Medicine, Fukui Medical University, Fukui, Japan; 6 Division of Clinical Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan; 7 Department of Hematology, Johann Wolfgang Goethe-University, Frankfurt, Germany
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 wild-type 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.<<
Innovive has Orphan Status for INNO-406. Here's the molecular structure:
kinasepro.wordpress.com
Cheers, Tuck |
