title: SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo.
abstract: FLT3 (fms-related tyrosine kinase/Flk2/Stk-2) is a receptor tyrosine kinase (RTK) primarily expressed on hematopoietic cells. In blasts from acute myelogenous leukemia (AML) patients, 2 classes of FLT3 activating mutations have been identified: 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 platelet-derived growth factor receptors, vascular endothelial growth factor receptors, and KIT. We show that SU11248 also has potent activity against wild-type FLT3 (FLT3-WT), FLT3-ITD, and FLT3 activation loop (FLT3-Asp835) 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 2 FLT3-ITD models: a subcutaneous tumor xenograft model and a bone marrow engraftment model. We show that SU11248 (20 mg/kg/d) dramatically regresses FLT3-ITD tumors in the subcutaneous tumor xenograft model and prolongs survival in the bone marrow engraftment model. Pharmacokinetic and pharmacodynamic analysis in subcutaneous 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.
authors.affiliation: Preclinical Research and Exploratory Development, SUGEN, South San Francisco, CA 94080, USA. marie-ofarrell@sugen.com
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: O'Farrell
authors.forename: Tinya J
authors.initials: TJ
authors.lastname: Abrams
authors.forename: Helene A
authors.initials: HA
authors.lastname: Yuen
authors.forename: Theresa J
authors.initials: TJ
authors.lastname: Ngai
authors.forename: Sharianne G
authors.initials: SG
authors.lastname: Louie
authors.forename: Kevin W H
authors.initials: KW
authors.lastname: Yee
authors.forename: Lily M
authors.initials: LM
authors.lastname: Wong
authors.forename: Weiru
authors.initials: W
authors.lastname: Hong
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Lee
authors.forename: Ajia
authors.initials: A
authors.lastname: Town
authors.forename: Beverly D
authors.initials: BD
authors.lastname: Smolich
authors.forename: William C
authors.initials: WC
authors.lastname: Manning
authors.forename: Lesley J
authors.initials: LJ
authors.lastname: Murray
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cherrington
mesh_terms: D000208:Acute Disease; D019943:Amino Acid Substitution; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D016026:Bone Marrow Transplantation; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D007951:Leukemia, Myeloid / Q000201:enzymology / Q000473:pathology; D008222:Lymphokines / Q000096:biosynthesis; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D017354:Point Mutation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D000077210:Sunitinib; D020080:Tandem Repeat Sequences; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000201:enzymology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3
chemical_list: D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D000077210:Sunitinib