936091-26-8

Details:

Fedratinib (SAR302503, TG101348) Basic information
Description In vitro In vivo
Product Name: Fedratinib (SAR302503, TG101348)
Synonyms: N-(1,1-Dimethylethyl)-3-[[5-methyl-2-[[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]amino]-4-pyrimidinyl]amino]benzenesulfonamide;TG-101348;N-TERT-BUTYL-3-(5-METHYL-2-(4-(2-(PYRROLIDIN-1-YL)ETHOXY)PHENYLAMINO)PYRIMIDIN-4-YLAMINO)BENZENESULFONAMIDE;BenzenesulfonaMide, N-(1,1-diMethylethyl)-3-[[5-Methyl-2-[[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]aMino]-4-pyriMidinyl]aMino]-;TG101348 (SAR302503);TG101348/TG-101348;SAR302503/TG101348;Fedratinib (SAR302503, TG101348)
CAS: 936091-26-8
MF: C27H36N6O3S
MW: 524.68
EINECS:
Product Categories: Inhibitor;Inhibitors
Mol File: 936091-26-8.mol
Fedratinib (SAR302503, TG101348) Structure
Fedratinib (SAR302503, TG101348) Chemical Properties
density  1.247
Safety Information
MSDS Information
Fedratinib (SAR302503, TG101348) Usage And Synthesis
Description 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.
In vitro 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.
In vivo 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.
Usage A potent, highly selective and ATP-competitive JAK2 inhibitor with an IC50 of 3 nM for JAK2 and JAK2V617F.