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|
|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.
|Solubility||DMSO 63 mg/mL|
 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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