title: UNC569, a novel small-molecule mer inhibitor with efficacy against acute lymphoblastic leukemia in vitro and in vivo.
abstract: Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although survival rates have improved, patients with certain biologic subtypes still have suboptimal outcomes. Current chemotherapeutic regimens are associated with short- and long-term toxicities and novel, less toxic therapeutic strategies are needed. Mer receptor tyrosine kinase is ectopically expressed in ALL patient samples and cell lines. Inhibition of Mer expression reduces prosurvival signaling, increases chemosensitivity, and delays development of leukemia in vivo, suggesting that Mer tyrosine kinase inhibitors are excellent candidates for targeted therapies. Brain and spinal tumors are the second most common malignancies in childhood. Multiple chemotherapy approaches and radiotherapies have been attempted, yet overall survival remains dismal. Mer is also abnormally expressed in atypical teratoid/rhabdoid tumors (AT/RT), providing a rationale for targeting Mer as a therapeutic strategy. We have previously described UNC569, the first small-molecule Mer inhibitor. This article describes the biochemical and biologic effects of UNC569 in ALL and AT/RT. UNC569 inhibited Mer activation and downstream signaling through ERK1/2 and AKT, determined by Western blot analysis. Treatment with UNC569 reduced proliferation/survival in liquid culture, decreased colony formation in methylcellulose/soft agar, and increased sensitivity to cytotoxic chemotherapies. MYC transgenic zebrafish with T-ALL were treated with UNC569 (4 μmol/L for two weeks). Fluorescence was quantified as indicator of the distribution of lymphoblasts, which express Mer and enhanced GFP. UNC569 induced more than 50% reduction in tumor burden compared with vehicle- and mock-treated fish. These data support further development of Mer inhibitors as effective therapies in ALL and AT/RT.
authors.affiliation: Corresponding Author: Douglas K. Graham, University of Colorado Anschutz Medical Campus, Mail Stop 8302, Building RC1-N, Room P18-4400, 12800 E. 19th Ave, Aurora, CO 80045. doug.graham@ucdenver.edu.
authors.forename: Sandra
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authors.lastname: Christoph
authors.forename: Deborah
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authors.lastname: Deryckere
authors.forename: Jennifer
authors.initials: J
authors.lastname: Schlegel
authors.forename: J Kimble
authors.initials: JK
authors.lastname: Frazer
authors.forename: Lance A
authors.initials: LA
authors.lastname: Batchelor
authors.forename: Alesia Y
authors.initials: AY
authors.lastname: Trakhimets
authors.forename: Susan
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authors.lastname: Sather
authors.forename: Debra M
authors.initials: DM
authors.lastname: Hunter
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Cummings
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Chao
authors.initials: C
authors.lastname: Yang
authors.forename: Dmitri
authors.initials: D
authors.lastname: Kireev
authors.forename: Catherine
authors.initials: C
authors.lastname: Simpson
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Norris-Drouin
authors.forename: Emily A
authors.initials: EA
authors.lastname: Hull-Ryde
authors.forename: William P
authors.initials: WP
authors.lastname: Janzen
authors.forename: Gary L
authors.initials: GL
authors.lastname: Johnson
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Frye
authors.forename: H Shelton
authors.initials: HS
authors.lastname: Earp
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Graham
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D058990:Molecular Targeted Therapy; D009374:Neoplasms, Experimental; D010766:Phosphorylation / Q000187:drug effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018335:Rhabdoid Tumor / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D013724:Teratoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015027:Zebrafish; D000076202:c-Mer Tyrosine Kinase
chemical_list: D000970:Antineoplastic Agents; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011743:Pyrimidines; C000589254:UNC569; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D051057:Proto-Oncogene Proteins c-akt