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Prepublished online as a Blood First Edition Paper on January 16, 2003; DOI 10.1182/blood-2002-07-2307. This Article Full Text (PDF) All Versions of this Article: 2002-07-2307v1 101/9/3597    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by O'Farrell, A.-M. Articles by Cherrington, J. M Search for Related Content PubMed PubMed Citation Articles by O'Farrell, A.-M. Articles by Cherrington, J. M Social Bookmarking                   What's this? Submitted July 31, 2002 Accepted November 14, 2002 SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo Anne-Marie O'Farrell*, Tinya J Abrams, Helene A Yuen, Theresa J Ngai, Sharianne G Louie, Kevin W H Yee, Lily M Wong, Weiru Hong, Leslie B Lee, Ajia Town, Beverly D Smolich, William C Manning, Lesley J Murray, Michael C Heinrich, and Julie M Cherrington Department of Preclinical Research & Exploratory Medicine, SUGEN Inc., South San Francisco, CA, USA Department of Medicine and OHSU Cancer Institute, Division of Hematology and Medical Oncology, Oregon Health and Science Univ & Portland VA Medical Center, Portland, OR, USA * Corresponding author; email: marie-ofarrell{at}sugen.com. FLT3 is a receptor tyrosine kinase (RTK) primarily expressed on hematopoietic cells. Two classes of FLT3 activating mutations have been identified in blasts from acute myelogenous leukemia (AML) patients: internal tandem duplication (ITD) mutations in the juxtamembrane domain (25-30% of patients) and point mutations in the kinase domain activation loop (7-8% of patients). FLT3-ITD mutations are the most common molecular defect identified in AML and have been shown to be an independent prognostic factor for decreased survival. FLT3-ITD is therefore an attractive molecular target for therapy. SU11248 is a recently described selective inhibitor with selectivity for split kinase domain RTKs, including PDGFR, VEGFR2 (Flk-1/ KDR) and KIT. We show that SU11248 also has potent activity against wild type FLT3 (FLT3-WT), FLT3-ITD and FLT3 activation loop (FLT3-D835) mutants in phosphorylation assays. SU11248 inhibits FLT3-driven phosphorylation and induces apoptosis in vitro. In addition, SU11248 inhibits FLT3-induced VEGF production. The in vivo efficacy of SU11248 was investigated in two FLT3-ITD models; a subcutaneous (SC) tumor xenograft model and a bone marrow engraftment model. We show that SU11248 (20mg/kg/day) dramatically regresses FLT3-ITD tumors in the SC tumor xenograft model and prolongs survival in the bone marrow engraftment model. Pharmacokinetic and pharmacodynamic (PK/PD) analysis in SC tumors showed that a single administration of an efficacious drug dose potently inhibits FLT3-ITD phosphorylation for up to 16 hours following a single dose. These results suggest that further exploration of SU11248 activity in AML patients is warranted. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: JNJ-28312141, a novel orally active colony-stimulating factor-1 receptor/FMS-related receptor tyrosine kinase-3 receptor tyrosine kinase inhibitor with potential utility in solid tumors, bone metastases, and acute myeloid leukemia Mol. 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Small In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects Blood, August 15, 2004; 104(4): 1145 - 1150. [Abstract] [Full Text] [PDF] J. A. Cain, J. L. Grisolano, A. D. Laird, and M. H. Tomasson Complete remission of TEL-PDGFRB-induced myeloproliferative disease in mice by receptor tyrosine kinase inhibitor SU11657 Blood, July 15, 2004; 104(2): 561 - 564. [Abstract] [Full Text] [PDF] B. D. Smith, M. Levis, M. Beran, F. Giles, H. Kantarjian, K. Berg, K. M. Murphy, T. Dauses, J. Allebach, and D. Small Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia Blood, May 15, 2004; 103(10): 3669 - 3676. [Abstract] [Full Text] [PDF] M. G. Mohi, C. Boulton, T.-L. Gu, D. W. Sternberg, D. Neuberg, J. D. Griffin, D. G. Gilliland, and B. G. 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Pryer Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with "standard of care" therapeutic agents for the treatment of breast cancer Mol. Cancer Ther., October 1, 2003; 2(10): 1011 - 1021. [Abstract] [Full Text] J. H. Antin A 41-Year-Old Woman With Chronic Myelogenous Leukemia JAMA, August 27, 2003; 290(8): 1083 - 1090. [Full Text] [PDF] B. Lowenberg, J. D. Griffin, and M. S. Tallman Acute Myeloid Leukemia and Acute Promyelocytic Leukemia Hematology, January 1, 2003; 2003(1): 82 - 101. [Abstract] [Full Text] [PDF]

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