Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera.
We report that TG101348, a selective small-molecule inhibitor of JAK2 with an in vitro IC50 of approximately 3 nM, shows therapeutic efficacy in a murine model of myeloproliferative disease induced by the JAK2V617F mutation. In treated animals, there was a statistically significant reduction in hematocrit and leukocyte count, a dose-dependent reduction/elimination of extramedullary hematopoiesis, and, at least in some instances, evidence for attenuation of myelofibrosis. There were no apparent toxicities and no effect on T cell number. In vivo responses were correlated with surrogate endpoints, including reduction/elimination of JAK2V617F disease burden assessed by quantitative genomic PCR, suppression of endogenous erythroid colony formation, and in vivo inhibition of JAK-STAT signal transduction as assessed by flow cytometric measurement of phosphorylated Stat5.
Wernig
Gerlinde
G
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Kharas
Michael G
MG
Okabe
Rachel
R
Moore
Sandra A
SA
Leeman
Dena S
DS
Cullen
Dana E
DE
Gozo
Maricel
M
McDowell
Elizabeth P
EP
Levine
Ross L
RL
Doukas
John
J
Mak
Chi Ching
CC
Noronha
Glenn
G
Martin
Michael
M
Ko
Yon D
YD
Lee
Benjamin H
BH
Soll
Richard M
RM
Tefferi
Ayalew
A
Hood
John D
JD
Gilliland
D Gary
DG
D019943:Amino Acid Substitution; D000818:Animals; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D003114:Colony-Forming Units Assay; D004195:Disease Models, Animal; D023381:Endpoint Determination; D005434:Flow Cytometry; D006413:Hematopoietic System / Q000166:cytology / Q000187:drug effects; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010649:Phenylalanine / Q000235:genetics; D011087:Polycythemia Vera / Q000188:drug therapy* / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015996:Survival Rate; D016896:Treatment Outcome; D014633:Valine / Q000235:genetics; D000096926:Benzenesulfonamides
D053614:Janus Kinase 2; D010649:Phenylalanine; D047428:Protein Kinase Inhibitors; D011759:Pyrrolidines; D013449:Sulfonamides; D014633:Valine; C528327:fedratinib; D000096926:Benzenesulfonamides