title: 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.
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 (IC(50)=11 and 18 nM, respectively), with significantly less activity against other kinases, including JAK3 (IC(50)=155 nM). CYT387 inhibits growth of Ba/F3-JAK2V617F and human erythroleukemia (HEL) cells (IC(50) approximately 1500 nM) or Ba/F3-MPLW515L cells (IC(50)=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 IC(50)=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.
authors.affiliation: Hematology Division, Mayo Clinic, Rochester, MN 55905, USA. pardanani.animesh@mayo.edu
authors.forename: A
authors.initials: A
authors.lastname: Pardanani
authors.forename: T
authors.initials: T
authors.lastname: Lasho
authors.forename: G
authors.initials: G
authors.lastname: Smith
authors.forename: C J
authors.initials: CJ
authors.lastname: Burns
authors.forename: E
authors.initials: E
authors.lastname: Fantino
authors.forename: A
authors.initials: A
authors.lastname: Tefferi
mesh_terms: D000483:Alleles; D000818:Animals; D045744:Cell Line, Tumor / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D003114:Colony-Forming Units Assay; D004353:Drug Evaluation, Preclinical; D004921:Erythropoietin / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology; D051379:Mice; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors; D011087:Polycythemia Vera / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D053628:Receptors, Thrombopoietin / Q000235:genetics; D050791:STAT Transcription Factors / Q000378:metabolism; D013379:Substrate Specificity; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D004921:Erythropoietin; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D053628:Receptors, Thrombopoietin; D050791:STAT Transcription Factors; C108603:TEL-JAK2 fusion protein, human; D000097764:ETS Translocation Variant 6 Protein; C082218:MPL protein, human; C406067:TEL-JAK3 protein, human; C507904:JAK1 protein, human; C507924:JAK2 protein, human