title: TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations.
abstract: JAK2V617F and MPLW515L/K represent recently identified mutations in myeloproliferative disorders (MPD) that cause dysregulated JAK-STAT signaling, which is implicated in MPD pathogenesis. We developed TG101209, an orally bioavailable small molecule that potently inhibits JAK2 (IC(50)=6 nM), FLT3 (IC(50)=25 nM) and RET (IC(50)=17 nM) kinases, with significantly less activity against other tyrosine kinases including JAK3 (IC(50)=169 nM). TG101209 inhibited growth of Ba/F3 cells expressing JAK2V617F or MPLW515L mutations with an IC(50) of approximately 200 nM. In a human JAK2V617F-expressing acute myeloid leukemia cell line, TG101209-induced cell cycle arrest and apoptosis, and inhibited phosphorylation of JAK2V617F, STAT5 and STAT3. Therapeutic efficacy of TG101209 was demonstrated in a nude mouse model. Furthermore, TG101209 suppressed growth of hematopoietic colonies from primary progenitor cells harboring JAK2V617F or MPL515 mutations.
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: A
authors.initials: A
authors.lastname: Pardanani
authors.forename: J
authors.initials: J
authors.lastname: Hood
authors.forename: T
authors.initials: T
authors.lastname: Lasho
authors.forename: R L
authors.initials: RL
authors.lastname: Levine
authors.forename: M B
authors.initials: MB
authors.lastname: Martin
authors.forename: G
authors.initials: G
authors.lastname: Noronha
authors.forename: C
authors.initials: C
authors.lastname: Finke
authors.forename: C C
authors.initials: CC
authors.lastname: Mak
authors.forename: R
authors.initials: R
authors.lastname: Mesa
authors.forename: H
authors.initials: H
authors.lastname: Zhu
authors.forename: R
authors.initials: R
authors.lastname: Soll
authors.forename: D G
authors.initials: DG
authors.lastname: Gilliland
authors.forename: A
authors.initials: A
authors.lastname: Tefferi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003114:Colony-Forming Units Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics*; D009196:Myeloproliferative Disorders / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011087:Polycythemia Vera / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D055728:Primary Myelofibrosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D053628:Receptors, Thrombopoietin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D013926:Thrombopoietin / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000096926:Benzenesulfonamides
chemical_list: D004791:Enzyme Inhibitors; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D011743:Pyrimidines; D053628:Receptors, Thrombopoietin; D050791:STAT Transcription Factors; D013449:Sulfonamides; D013926:Thrombopoietin; D051941:fms-Like Tyrosine Kinase 3; C522865:TG101209; D000096926:Benzenesulfonamides; C082218:MPL protein, human; C497970:FLT3 protein, human