Home JAK/STAT JAK inhibitor BMS-911543

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BMS-911543 JAK inhibitor

Cat.No.S7144

BMS-911543 is a potent and selective inhibitor of JAK2 with IC50 of 1.1 nM, ~350-, 75- and 65-fold selective to JAK1, JAK3 and TYK2, respectively. Phase 1/2.
BMS-911543 JAK inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 432.52

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Chemical Information, Storage & Stability

Molecular Weight 432.52 Formula

C23H28N8O

 Storage (From the date of receipt)
CAS No. 1271022-90-2 Download SDF Storage of Stock Solutions

Solubility

In vitro
Batch:

DMSO : 35 mg/mL (80.92 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Ethanol : 33 mg/mL

Water : Insoluble

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Mass Concentration Volume Molecular Weight

In vivo
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Mechanism of Action

Targets/IC50/Ki
JAK2 [1]
(Cell-free assay)
1.1 nM
SET-2 [1]
(Cell-free assay)
60 nM
TYK2 [1]
(Cell-free assay)
66 nM
JAK3 [1]
(Cell-free assay)
75 nM
In vitro
BMS-911543 shows potent antiproliferative activity in the SET-2 as well as BaF3-V617F engineered cell lines (both dependent upon JAK2 pathway), with IC50 values of 60 and 70 nM, respectively. The antiproliferative activity of this compound in SET-2 and BaF3-V617F cells correlates with similar activity on constitutively active pSTAT5 (IC50 80 and 65 nM, respectively). In contrast, non-JAK2-dependent cell lines (A549, MDA-MB-231, MiaPaCa-2) are significantly less sensitive to the inhibitor treatment. The excellent biochemical selectivity versus JAK1/3 translates to good cellular and functional selectivity in an IL-2 mediated T-cell proliferation assay (IC50 990 nM). Also, cell lines that rely on other JAK family members, including CTLL2 and parental BaF3 cells stimulated with IL-3, shows weak antiproliferative activity for this chemical (IC50 2.9 and 3.5 μM, respectively)[1].
In vivo
BMS-911543 suppresses the pSTAT5 levels (mediated by wild type JAK2) relative to vehicle control when stimulated with thrombopoetin (TPO) in a mouse pharmacodynamic model. The responses are dose dependent and results in nearly complete normalization of pSTAT5 levels for 18 h at the highest oral dose of 30 mg/kg. At an intermediate 10 mg/kg oral dose, ∼65% reduction is observed up to 18 h, whereas at the 5 mg/kg dose, approximately 50% reduction in pSTAT5 for 8 h is achieved. Observed pSTAT5 reductions correlates with exposures of this compound, with AUC0–8h values of 23, 41, and 109 μM·h, respectively, for dose levels of 5, 10, and 30 mg/kg. In addition, this chemical demonstrates a potent and sustained (2 mg/kg up to 7 h) PD effect in blocking pSTAT5 formation in mice grafted with human SET-2 cells harboring JAK2-V617F mutation. The absolute oral bioavailability in solution is >50% in mice, rats, dogs, and monkeys. In addition, the absorption of this compound is not significantly impacted by particle dissolution (suspension formulation), with a relative bioavailability (vs solution) of ∼60% in rats and ∼100% in dogs[1].
References

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01236352 Terminated
Cancer
Bristol-Myers Squibb
 April 7 2011 Phase 1|Phase 2

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