title: Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapy.
abstract: Activating mutations in FLT3 confer poor prognosis for individuals with acute myeloid leukemia (AML). Clinically active investigational FLT3 inhibitors can achieve complete remissions but their utility has been hampered by acquired resistance and myelosuppression attributed to a 'synthetic lethal toxicity' arising from simultaneous inhibition of FLT3 and KIT. We report a novel chemical strategy for selective FLT3 inhibition while avoiding KIT inhibition with the staurosporine analog, Star 27. Star 27 maintains potency against FLT3 in proliferation assays of FLT3-transformed cells compared with KIT-transformed cells, shows no toxicity towards normal human hematopoiesis at concentrations that inhibit primary FLT3-mutant AML blast growth, and is active against mutations that confer resistance to clinical inhibitors. As a more complete understanding of kinase networks emerges, it may be possible to define anti-targets such as KIT in the case of AML to allow improved kinase inhibitor design of clinical agents with enhanced efficacy and reduced toxicity.
authors.affiliation: Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Warkentin
authors.affiliation: Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lopez
authors.affiliation: Division of Hematology and Oncology, University of California, San Francisco, San Francisco, United States.
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Lasater
authors.affiliation: Division of Hematology and Oncology, University of California, San Francisco, San Francisco, United States.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Lin
authors.affiliation: Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Bai-Liang
authors.initials: BL
authors.lastname: He
authors.affiliation: Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Anskar Yh
authors.initials: AY
authors.lastname: Leung
authors.affiliation: Division of Hematology and Oncology, University of California, San Francisco, San Francisco, United States.
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Smith
authors.affiliation: Division of Hematology and Oncology, University of California, San Francisco, San Francisco, United States.
authors.forename: Neil P
authors.initials: NP
authors.lastname: Shah
authors.affiliation: Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States.
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D001855:Bone Marrow Diseases / Q000139:chemically induced*; D045744:Cell Line, Tumor; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008954:Models, Biological; D009154:Mutation; D013329:Structure-Activity Relationship; D015027:Zebrafish; D051941:fms-Like Tyrosine Kinase 3 / Q000187:drug effects* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
keywords: FLT3; KIT; biochemistry; chemical synthesis; human biology; leukemia; medicine; protein kinase; staurosporine; zebrafish