Fedratinib (SAR302503, TG101348)
Molecular Weight(MW): 524.68
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.
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|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.|
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. |
Cell-free Kinase Activity Assays:IC50 values for TG101348 are determined commercially using the InVitrogen kinase profiling service for a 223 kinase screen that included JAK2 and JAK2V617F or Carna Biosciences for the screen of all Janus kinase family members including JAK1 and Tyk2. ATP concentration is set to approximately the Km value for each kinase.
|In vitro||DMSO||100 mg/mL (190.59 mM)|
|In vivo||Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
1% DMSO+30% polyethylene glycol+1% Tween 80
For best results, use promptly after mixing.
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Clinical Trial Information
|NCT Number||Recruitment||interventions||Conditions||Sponsor/Collaborators||Start Date||Phases|
|NCT03983161||Not yet recruiting||Drug: Fedratinib||Healthy Volunteers|Hepatic Impairment||Celgene|Impact Biomedicines Inc. a wholly owned subsidiary of Celgene Corporation||December 15 2019||Phase 1|
|NCT03983239||Not yet recruiting||Drug: Fedratinib|Drug: Rifampin|Drug: Rifabutin||Healthy Volunteers||Celgene|Impact Biomedicines Inc. a wholly owned subsidiary of Celgene Corporation||December 15 2019||Phase 1|
|NCT02596347||Unknown status||Procedure: Blood draw|Procedure: bronchoscopy||Chronic Beryllium Disease (CBD)|Beryllium Sensitization (BeS)||National Jewish Health||April 2015||--|
|NCT01692366||Completed||Drug: SAR302503||Myelofibrosis||Sanofi||November 2012||Phase 2|
|NCT01523171||Completed||Drug: SAR302503||Hematopoietic Neoplasm||Sanofi||April 2012||Phase 2|
Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.
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