BMS-911543

Cell lines

SET2 and Ba/F3 cells engineered to express JAK2V617F; human platelets; primary hematopoetic progenitor cells isolated from MPN patients that expressed JAK2V617F, JAK2EXON12 or MPLW515L mutations

Preparation method

This compound is soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

0-10 μM; 6, 16 or 24 h

Applications

In SET2 and Ba/F3 cells engineered to express JAK2V617F, BMS-911543 exhibited a dose-dependent anti-proliferative effect with IC50 values of 60 and 70 nM, respectively. In human platelets, BMS-911543 inhibited TPO-stimulated pSTAT5 in a dose-dependent manner. In primary hematopoetic progenitor cells isolated from MPN patients that expressed JAK2V617F, JAK2EXON12 or MPLW515L mutations, BMS-911543 inhibited EPO-mediated burst forming unit-erythroid (BFU-E) colony growth with IC50 ranging from <0.150 to ~0.9 μM.

Animal models

BALB/c mice; athymic mice xenografted with SET2 cells

Dosage form

5, 10 and 30mg/kg, 18h; 1, 2, 5 and 10 mg/kg, orally administered

Application

In BALB/c mice treated with BMS-911543, platelets were isolated and treated with TPO to induce the pSTAT5. At 30mg/kg, BMS-911543 fully suppressed pSTAT5 induction at all time points (1–18 h post dose). BMS-911543 induced ~75% reduction up to 18 h at 10mg/kg. 5mg/kg BMS-911543 revealed a roughly 50% reduction in TPO-stimulated pSTAT5 by ~8 h. In athymic mice xenografted with SET2 cells, 10mg/kg BMS-911543 showed 90–100% inhibition of pSTAT5 up to 7 h post dose.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1] Purandare AV, McDevitt TM, Wan H, You D, Penhallow B, Han X, Vuppugalla R, Zhang Y, Ruepp SU, Trainor GL, Lombardo L, Pedicord D, Gottardis MM, Ross-Macdonald P, de Silva H, Hosbach J, Emanuel SL, Blat Y, Fitzpatrick E, Taylor TL, McIntyre KW, Michaud E, Mulligan C, Lee FY, Woolfson A, Lasho TL, Pardanani A, Tefferi A, Lorenzi MV. Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2. Leukemia. 2012 Feb;26(2):280-8.

[2]. Wan H1, Schroeder GM1, Hart AC1, et al. Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms. ACS Med Chem Lett. 2015 Jul 12;6(8):850-5.