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Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: implications for the treatment of myeloproliferative neoplasms

Alfonso Quintás-Cardama, Kris Vaddi, Phillip Liu, Taghi Manshouri, Jun Li, Peggy A. Scherle, Eian Caulder, Xiaoming Wen, Yanlong Li, Paul Waeltz, Mark Rupar, Timothy Burn, Yvonne Lo, Jennifer Kelley, Maryanne Covington, Stacey Shepard, James D. Rodgers, Patrick Haley, Hagop Kantarjian, Jordan S. Fridman and Srdan Verstovsek

Abstract

Constitutive JAK2 activation in hematopoietic cells by the JAK2V617F mutation recapitulates myeloproliferative neoplasm (MPN) phenotypes in mice, establishing JAK2 inhibition as a potential therapeutic strategy. While most patients with polycythemia vera carry the JAK2V617F mutation, half of those with essential thrombocythemia or primary myelofibrosis do not, suggesting alternative mechanisms for constitutive activation of JAK-STAT signaling in MPNs. Recent evidence indicates that most patients with primary myelofibrosis have elevated levels of JAK-dependent pro-inflammatory cytokines (e.g. interleukin-6) consistent with the observation of JAK1 hyperactivation in MPN patients. Accordingly, we evaluated the effectiveness of selective JAK1/2 inhibition in experimental models relevant for the treatment of MPNs and report on the in vitro and in vivo effects of INCB018424, the first potent, selective, oral JAK1/JAK2 inhibitor to enter the clinic. INCB018424 inhibited interleukin-6 signaling (IC50 281nM), and proliferation of JAK2V617F-positive Ba/F3 cells (IC50 127nM). In primary cultures, INCB018424 preferentially suppressed erythroid progenitor colony formation from JAK2V617F-positive polycythemia vera patients (IC50 67nM) vs. healthy donors (IC50 >400nM). In a mouse model of JAK2V617F-positive MPN, oral INCB018424 markedly reduced splenomegaly and circulating levels of inflammatory cytokines, and preferentially eliminated neoplastic cells, resulting in significantly prolonged survival without myelosuppressive or immunosuppressive effects. Preliminary clinical results support these preclinical data and establish INCB018424 as a promising oral agent for the treatment of MPNs.

  • Submitted April 6, 2009.
  • Accepted January 18, 2010.