AT9283, a potent inhibitor of the Aurora kinases and Jak2, has therapeutic potential in myeloproliferative disorders.
Constitutive activation of Janus kinase (Jak) 2 is the most prevalent pathogenic event observed in the myeloproliferative disorders (MPD), suggesting that inhibitors of Jak2 may prove valuable in their management. Inhibition of the Aurora kinases has also proven to be an effective therapeutic strategy in a number of haematological malignancies. AT9283 is a multi-targeted kinase inhibitor with potent activity against Jak2 and Aurora kinases A and B, and is currently being evaluated in clinical trials. To investigate the therapeutic potential of AT9283 in the MPD we studied its activity in a number of Jak2-dependent systems. AT9283 potently inhibited proliferation and Jak2-related signalling in Jak2-dependent cell lines as well as inhibiting the formation of erythroid colonies from haematopoietic progenitors isolated from MPD patients with Jak2 mutations. The compound also demonstrated significant therapeutic potential in vivo in an ETV6-JAK2 (TEL-JAK2) murine leukaemia model. Inhibition of both Jak2 and Aurora B was observed in the model systems used, indicating a dual mechanism of action. Our results suggest that AT9283 may be a valuable therapy in patients with MPD and that the dual inhibition of Jak2 and the Aurora kinases may potentially offer combinatorial efficacy in the treatment of these diseases.
Dawson
Mark A
MA
Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
Curry
Jayne E
JE
Barber
Kelly
K
Beer
Philip A
PA
Graham
Brent
B
Lyons
John F
JF
Richardson
Caroline J
CJ
Scott
Mike A
MA
Smyth
Tomoko
T
Squires
Matthew S
MS
Thompson
Neil T
NT
Green
Anthony R
AR
Wallis
Nicola G
NG
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D015672:Erythroid Precursor Cells / Q000187:drug effects; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
C535237:1-cyclopropyl-3-(3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl)urea; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D014508:Urea; D053614:Janus Kinase 2; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases