product name XL019
Description: XL019 is a potent and selective JAK2 inhibitor with IC50 of 2.2 nM, exhibiting >50-fold selectivity over JAK1, JAK3 and TYK2. XL019 is an orally bioavailable JAK2 inhibitor with potential antineoplastic activity. XL019 inhibits the activation of JAK2 as well as the mutated form JAK2V617F, which may result in the inhibition of the JAK-STAT signaling pathway and may induce apoptosis. The JAK2 mutated form JAK2V617F has a valine-to-phenylalanine modification at position 617 and plays a key role in tumor cell proliferation and survival.
References: Bioorg Med Chem Lett. 2012 Dec 15;22(24):7653-8; Hematology Am Soc Hematol Educ Program. 2009:636-42.
444.53
Formula
C25H28N6O2
CAS No.
945755-56-6
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 16 mg/mL (36.0 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
Synonyms
other peoduct :
| In Vitro |
In vitro activity: XL019 is a highly selective JAK2 inhibitor, binds to the active site of JAK2 displaying >50-fold selectivity against JAK1 and TYK2. XL019 reveals a desirable CYP (1A2, 2C9, 2D6, 3A4 ≥20 μM), hERG (16 μM), and P-glycoprotein inhibition (>20 μM) profile. XL019 inhibits the activation of JAK2 as well as the mutated form JAK2V617F, which may result in the inhibition of the JAK-STAT signaling pathway and may induce apoptosis. XL019 showed more than 10-fold selective inhibition (IC50 = 64 nM) of STAT5 phosphorylation following EPO stimulation of erythroid cells compared with other cell systems. Kinase Assay: Analogue XL019 was also evaluated against a selectivity panel of 118 kinases. Targets for which XL019 exhibited IC50 <1000 nM are displayed. Overall XL019 is a highly selective JAK2 inhibitor displaying >50-fold selectivity against all kinases tested including JAK family members JAK1 and TYK2. Further in vitro evaluation of XL019 revealed that it demonstrated a desirable CYP (1A2, 2C9, 2D6, 3A4 ?20 μM), hERG (16 μM), and P-glycoprotein inhibition (>20 μM) profile. Cell Assay: XL019 shows good biochemical and cellular potency against JAK2 with good selectivity, against a panel of over 100 serine/threonine and tyrosine kinases, including other members of the JAK family [2]. Analogue XL019 was evaluated against a select panel of 118 kinases. Targets for which XL019 exhibited IC50 <1000 nM are displayed. XL019 is a highly selective JAK2 inhibitor displaying >50-fold selectivity against all kinases tested including JAK1 and TYK2. XL019 was a desirable CYP, hERG (16 μM), and P-glycoprotein inhibition (>20 μM). |
|---|---|
| In Vivo | XL019 significantly inhibits downstream markers pSTAT1 and pSTAT3 after administration 30, 100, and 300 mg/kg resulting in an ED50 of 42 mg/kg (pSTAT1) and 210 mg/kg (pSTAT3). XL019 has a superior pharmacodynamic profile and exhibits good oral absorption, and modest clearance and half life across species. XL019 inhibits of HEL.92.1.7 xenograft tumors growth in mice. It demonstrates 60% and 70% inhibition when dosed orally at 200 mg/kg and 300 mg/kg respectively twice a day for 14 days. Dosing at 300 mg/kg bid provided an 11.3-fold increase in apoptosis relative to vehicle control. |
| Animal model | HEL.92.1.7 xenograft |
| Formulation & Dosage | Dissolved in water (10 mM HCl); 100, 200, 300 mg/kg; oral gavage |
| References | Bioorg Med Chem Lett. 2012 Dec 15;22(24):7653-8; Hematology Am Soc Hematol Educ Program. 2009:636-42. |
