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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Quality Control

Batch: Purity: 99.03%
99.03

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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In vivo
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Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

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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

Mechanism of Action

Targets/IC50/Ki
JAK2
(Cell-free assay)
1.1 nM
SET-2
(Cell-free assay)
60 nM
TYK2
(Cell-free assay)
66 nM
JAK3
(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).
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.
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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