Abstract
Somatic mutations in Janus kinase 2 (JAK2), including JAK2V617F, result in dysregulated JAK-signal transducer and activator transcription (STAT) signaling, which is implicated in myeloproliferative neoplasm (MPN) pathogenesis. CYT387 is an ATP-competitive small molecule that potently inhibits JAK1/JAK2 kinases (IC50=11 and 18 nM, respectively), with significantly less activity against other kinases, including JAK3 (IC50=155 nM). CYT387 inhibits growth of Ba/F3-JAK2V617F and human erythroleukemia (HEL) cells (IC50 ∼1500 nM) or Ba/F3-MPLW515L cells (IC50=200 nM), but has considerably less activity against BCR–ABL harboring K562 cells (IC=58 000 nM). Cell lines harboring mutated JAK2 alleles (CHRF-288-11 or Ba/F3-TEL-JAK2) were inhibited more potently than the corresponding pair harboring mutated JAK3 alleles (CMK or Ba/F3-TEL-JAK3), and STAT-5 phosphorylation was inhibited in HEL cells with an IC50=400 nM. Furthermore, CYT387 selectively suppressed the in vitro growth of erythroid colonies harboring JAK2V617F from polycythemia vera (PV) patients, an effect that was attenuated by exogenous erythropoietin. Overall, our data indicate that the JAK1/JAK2 selective inhibitor CYT387 has potential for efficacious treatment of MPN harboring mutated JAK2 and MPL alleles.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Levine RL, Pardanani A, Tefferi A, Gilliland DG . Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer 2007; 7: 673–683.
Tefferi A, Vardiman JW . Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 2008; 22: 14–22.
Rollison DE, Howlader N, Smith MT, Strom SS, Merritt WD, Ries LA et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001–2004, using data from the NAACCR and SEER programs. Blood 2008; 112: 45–52.
Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 2007; 356: 459–468.
Tiedt R, Hao-Shen H, Sobas MA, Looser R, Dirnhofer S, Schwaller J et al. Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood 2008; 111: 3931–3940.
Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344: 1031–1037.
Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003; 348: 1201–1214.
Apperley JF, Gardembas M, Melo JV, Russell-Jones R, Bain BJ, Baxter EJ et al. Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med 2002; 347: 481–487.
Pardanani A . JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials. Leukemia 2008; 22: 23–30.
Lasho TL, Tefferi A, Hood JD, Verstovsek S, Gilliland DG, Pardanani A . TG101348, a JAK2-selective antagonist, inhibits primary hematopoietic cells derived from myeloproliferative disorder patients with JAK2V617F, MPLW515K or JAK2 exon 12 mutations as well as mutation negative patients. Leukemia 2008; 22: 1790–1792.
Pardanani A, Hood J, Lasho T, Levine RL, Martin MB, Noronha G et al. TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. Leukemia 2007; 21: 1658–1668.
Wernig G, Kharas MG, Okabe R, Moore SA, Leeman DS, Cullen DE et al. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell 2008; 13: 311–320.
Lacronique V, Boureux A, Monni R, Dumon S, Mauchauffe M, Mayeux P et al. Transforming properties of chimeric TEL-JAK proteins in Ba/F3 cells. Blood 2000; 95: 2076–2083.
Lasho TL, Pardanani A, McClure RF, Mesa RA, Levine RL, Gilliland DG et al. Concurrent MPL515 and JAK2V617F mutations in myelofibrosis: chronology of clonal emergence and changes in mutant allele burden over time. Br J Haematol 2006; 135: 683–687.
Lasho TL, Tefferi A, Hood JD, Verstovsek S, Gilliland DG, Pardanani A . TG101348, a JAK2-selective antagonist, inhibits primary hematopoietic cells derived from myeloproliferative disorder patients with JAK2V617F, MPLW515K or JAK2 exon 12 mutations as well as mutation negative patients. Leukemia 2008; 22:1790–1792.
Fridman J, Nussenzveig R, Liu P, Rodgers J, Burn T, Haley P et al. Discovery and preclinical characterization of INCB018424, a selective JAK2 inhibitor for the treatment of myeloproliferative disorders. Blood (ASH Annu Meet Abstr) 2007; 110: 3538.
Paquette R, Sokol L, Shah NP, Silver RT, List AF, Clary DO et al. A phase I study of XL019, a selective JAK2 inhibitor, in patients with polycythemia vera. Blood (ASH Annu Meet Abstr) 2008; 112: 2810.
Dobrzanski P, Hexner E, Serdikoff C, Jan M, Swider C, Robinson C et al. CEP-701 is a JAK2 inhibitor which attenuates JAK2/STAT5 signaling pathway and the proliferation of primary cells from patients with myeloproliferative disorders. Blood (ASH Annu Meet Abstr) 2006; 108: 3594.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Pardanani, A., Lasho, T., Smith, G. et al. CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia 23, 1441–1445 (2009). https://doi.org/10.1038/leu.2009.50
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/leu.2009.50