TG-101348 CAS NO.936091-26-8

tg-101348的生物活性

tg-101348 (sar302503) is a selective inhibitor of jak2 with ic50 of 3 nm, 35- and 334-fold more selective for jak2 versus jak1 and jak3, tg-101348 also inhibit brd4 with ic50 of 340 nm.
ic50 value: 3 nm (jak2); 340 nm (brd4) [1] [4]
target: jak2; brd4
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 [1]. 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 [2]. 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 [3]. tg101348 also is a inhibitor of brd4 with ic50 of 340 nm [4].
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 [1]. oral administration of tg101348 (120 mg/kg) significantly inhibits pv progenitor erythroid differentiation in vivo [2].