title: LS104, a non-ATP-competitive small-molecule inhibitor of JAK2, is potently inducing apoptosis in JAK2V617F-positive cells.
abstract: The activating JAK2V617F mutation has been described in the majority of patients with BCR-ABL-negative myeloproliferative disorders (MPD). In this report, we characterize the small-molecule LS104 as a novel non-ATP-competitive JAK2 inhibitor: Treatment of JAK2V617F-positive cells with LS104 resulted in dose-dependent induction of apoptosis and inhibition of JAK2 autophosphorylation and of downstream targets. Activation of these targets by JAK2 was confirmed in experiments using small interfering RNA. LS104 inhibited JAK2 kinase activity in vitro. This effect was not reversible using elevated ATP concentrations, whereas variation of the kinase substrate peptide led to modulation of the IC50 value for LS104. In line with these data, combination treatment using LS104 plus an ATP-competitive JAK2 inhibitor (JAK inhibitor I) led to synergistically increased apoptosis in JAK2V617F-positive cells. Furthermore, LS104 strongly inhibited cytokine-independent growth of endogenous erythroid colonies isolated from patients with JAK2V617F-positive MPD in vitro, whereas there was no significant effect on growth of myeloid colonies obtained from normal controls. Based on these data, we have recently started a phase I clinical trial of LS104 for patients with JAK2V617F-positive MPDs. To the best of our knowledge, this is the first report on a non-ATP-competitive kinase inhibitor being tested in a clinical trial.
authors.affiliation: 3rd Medical Department, Johannes Gutenberg University, Langenbeckstrabe 1, 55101 Mainz, Germany.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Lipka
authors.forename: Linda S
authors.initials: LS
authors.lastname: Hoffmann
authors.forename: Florian
authors.initials: F
authors.lastname: Heidel
authors.forename: Boyka
authors.initials: B
authors.lastname: Markova
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Blum
authors.forename: Frank
authors.initials: F
authors.lastname: Breitenbuecher
authors.forename: Stefan
authors.initials: S
authors.lastname: Kasper
authors.forename: Thomas
authors.initials: T
authors.lastname: Kindler
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Christoph
authors.initials: C
authors.lastname: Huber
authors.forename: Thomas
authors.initials: T
authors.lastname: Fischer
mesh_terms: D000181:Acrylonitrile / Q000031:analogs & derivatives* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020014:K562 Cells; D051379:Mice; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction; D013343:Styrenes / Q000494:pharmacology*
chemical_list: C530802:2-(benzylaminocarbonyl)-3-(3,4-dihydroxystyryl)acrylonitrile; D047428:Protein Kinase Inhibitors; D013343:Styrenes; D000255:Adenosine Triphosphate; D053614:Janus Kinase 2; D000181:Acrylonitrile