936091-26-8 CAS NO.936091-26-8

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.