Momelotinib (CYT387) is a small-molecule, ATP-competitive JAK1/JAK2 inhibitor with IC50 of 11 and 18 nM respectively. CYT387 inhibits growth of Ba/F3-JAK2V617F and human erythroleukemia (HEL) cells (IC (50) approximately 1500 nM) or Ba/F3-MPLW515L cells (IC (50)=200 nM), but has considerably less activity against BCR-ABL harboring K562 cells (IC50=58000 nM).
|Source||Pharmacol Res (2013). Figure 3. CYT387|
|Incubation Time||24 h|
|Results||Neither absence of Mdr1a/1bnor of Bcrp1 showed a significant effect on the overall plasma expo-sure between 0 and 8 h.|
|Source||Pharmacol Res (2013). Figure 2. CYT387|
|Cell Lines||MDCK-II cells|
|Incubation Time||2,4 and 8 h|
|Results||In the MDCKII parental cell line, there was a mod-est apically directed transport of CYT387 (transport ratio r = 1.2),which was abrogated with the MDR1-specific inhibitor zosuquidar(Fig. 2A and B), suggesting that this background transport wasmediated by endogenous canine MDR1 present in the MDCKII cells.|
|Cell lines||Ba/F3 cells expressing JAK2V617F (Ba/F3-JAK2V617F) and MPLW515L (Ba/F3–MPLW515L) mutants, as well as CHRF-288-11 (JAK2T875N) and CMK (JAK3A572V) cells|
|Preparation method||Cell-based assays. Ba/F3 cells expressing JAK2V617F (Ba/F3-JAK2V617F) and MPLW515L (Ba/F3–MPLW515L) mutants, as well as CHRF-288-11 (JAK2T875N) and CMK (JAK3A572V) cells were generously provided by D Gary Gilliland (Brigham and Women’s Hospital, Boston, MA, USA). The TEL/JAK2 and TEL/ JAK3 fusions were generated and introduced into Ba/F3 murine cells as described earlier. The TEL/JAK2- or TEL/JAK3-transfected cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) containing 10% fetal calf serum (FCS). Ba/F3 wild-type cells were cultured in RPMI containing 10% FCS supplemented with 5 ng/ml murine IL-3 (Peprotech, Rocky Hill, NJ, USA). Proliferation was measured using the Alamar Blue assay (TREK Diagnostic Systems, Cleveland, OH, USA) after incubating for 72 h at 37℃with 5% CO2.|
|Incubation time||72 h|
|Animal models||murine model of JAK2V617F-dependent MPN|
|Formulation||dissolved in NMP (120 mg/mL final; 1-methyl-2-pyrrolidinone, Chromasolv Plus; Sigma-Aldrich). Subsequently, the CYT387/NMP mix was diluted with 0.14M Captisol (Cydex Pharmaceuticals Inc) to a concentration of 6 mg/mL and further diluted with 0.1M Captisol to a final concentration of 4 mg/mL.|
|Dosages||25, 50mg/kg twice daily from day 34 to day 82|
|Solubility (25°C)||DMSO 63 mg/mL|
Powder -20°C 3 years ; 4°C 2 years
In solvent -80°C 6 months ; -20°C 1 month
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
 Sparidans et al. J Chromatogr B Analyt Technol Biomed Life Sci. Liquid chromatography-tandem mass spectrometric assay for the JAK2 inhibitor CYT387 in plasma.
 Monaghan et al. Leukemia. The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells.
 Tyner et al. Blood. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms.
 Pardanani et al. Leukemia. CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients.
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