Fedratinib (SAR302503, TG101348) is a selective inhibitor of JAK2 with IC50 of 3 nM in cell-free assays, 35-and 334-fold more selective for JAK2 versus JAK1 and JAK3. Phase 2.
TG-101348 also significantly inhibits JAK2 V617F, Flt3, and Ret with IC50 of 3 nM, 15 nM, and 48 nM, respectively. TG101348 has an IC50 ~300-fold higher for the closely related JAK3 and is a less potent inhibitor of the JAK1 and TYK2 family members. TG101348 inhibits proliferation of a human erythroblast leukemia (HEL) cell line that harbors the JAK2V617F mutation, as well as a murine pro-B cell line expressing human JAK2V617F (Ba/F3 JAK2V617F), with IC50 of 305 nM and 270 nM, respectively. TG-101348 also inhibits proliferation of parental Ba/F3 cells to a comparable level, with IC50 of ~420 nM. TG101348 treatment reduces STAT5 phosphorylation at concentrations that parallel the concentrations required to inhibit cell proliferation. TG101348 induces apoptosis in both HEL and Ba/F3 JAK2V617F cells in a dose-dependent manner. TG101348 does not show proapoptotic activity in control normal human dermal fibroblasts at concentrations up to 10 μM, and the antiproliferative IC50 against fibroblasts is >5 μM. TG101348 treatment decreases GATA-1 expression, which is associated with erythroid-skewing of JAK2V617F+ progenitor differentiation, and inhibits STAT5 as well as GATA S310 phosphorylation. TG101348 inhibits the proliferation of HMC-1.1 (KITV560G) cells, with somewhat lower potency than HMC-1.2 (KITD816V, KITV560G) cells, with IC50 of 740 nM and 407 nM, respectively.
TG101348 has potential for efficacious treatment of JAK2V617F-associated myeloproliferative diseases (MPD). In treated animals, there is 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, correlated with surrogate endpoints, including reduction/elimination of JAK2V617F disease burden, suppression of endogenous erythroid colony formation, and in vivo inhibition of JAK-STAT signal transduction. There are no apparent toxicities and no effect on T cell number. Oral administration of TG101348 (120 mg/kg) significantly inhibits PV progenitor erythroid differentiation in vivo.
Class: non-receptor tyrosine kinase
Treatment: myeloproliferative diseases
Oral bioavailability = 18–37%
Elimination half-life = 2–3 days
Protein binding = 91–96%
TG101348 is a selective inhibitor of JAK2 tyrosine kinase. Potent JAK2 inhibitor.
A potent, highly selective and ATP-competitive JAK2 inhibitor with an IC50 of 3 nM for JAK2 and JAK2V617F.
ChEBI: N-tert-butyl-3-[[5-methyl-2-[4-[2-(1-pyrrolidinyl)ethoxy]anilino]-4-pyrimidinyl]amino]benzenesulfonamide is a sulfonamide.
Pharmaceutical Applications
Fedratinib is a JAK2 inhibitor approved for the treatment of intermediate-2 or high-risk primary or secondary myelofibrosis in adult patients.
tg101348, also known as sar302503, is a potent and selective inhibitor of janus kinase 2 (jak2), one member of a family of 4 cytoplasmic tyrosine kinases including janus kinase 1(jak1), jak2, janus kinase 3 (jak3) and tyrosine kinase 2 (tyk2), with the inhibition constant ic50 of 3 nm. comparing to other close related kinases, the selectivity of tg101348 for jak2 is 35- and 334-fold stronger than that for jak3 and jak1 respectively. tg10348 is capable of inducing apoptosis in hel cells as well baf/3 cells harboring jak2v617 mutation and inhibiting hematopoietic progenitor colony formation and erythroid engraftment in samples from polycythemia vera (pv) patients.srdan verstovsek. therapeutic potential of jak2 inhibitors. hematology am soc hematol educ program 2009:636-642
Fedratinib pharmacokinetics are characterized by prolonged duration of action: effective half-life of 41 hours, terminal half-life of approximately 114 hours, and elimination half-life of 2–3 days, which makes it suitable for once-daily dosing. In contrast, ruxolitinib has a short terminal half-life of approximately 3 h, suggesting that twice-daily administration of ruxolitinib is more suitable than once-daily dosing. Following oral administration, fedratinib is mainly bio-oxidized by CYP3A4 to give two major circulating metabolites in the plasma: the pyrrolidone derivative 1 and the N-butyric acid 2.
Fedratinib was readily synthesized in two steps based on the metal-catalyzed coupling reaction and the acid-mediated SNAr reaction. The synthetic route developed by TargeGen Inc. in 2011 is depicted in the piture below. Compound 302 was prepared from pyrimidine 300 and 3-bromo-N-(tert-butyl)benzenesulfonamide 301 under coupling conditions employing Pd2(dba)3 and Xantphos. Compound 302 next underwent microwave assisted SNAr reaction with fragment 303 to afford fedratinib in 27% yield.
